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MitImpact 2

MitImpact is a collection of pre-computed pathogenicity predictions for all possible nucleotide changes that cause non-synonymous substitution in human mitochondrial protein coding genes. The new version 2.5 greatly updates the tool published in (PMID: 25516408) with the features and contents below.

User guide

Search by Genomic position

Genomic positions

Search by dbSNP ID

dbSNP ID

Search by Gene or Protein position

Gene or Protein position

List of mitochondrial gene and protein identifiers

# Gene Symbol Ensembl Gene ID Ensembl Protein ID Uniprot Name Uniprot ID Ncbi Gene ID Ncbi Protein ID
1 MT-ND1 ENSG00000198888 ENSP00000354687 NU1M_HUMAN P03886 4535 YP_003024026.1
2 MT-ND2 ENSG00000198763 ENSP00000355046 NU2M_HUMAN P03891 4536 YP_003024027.1
3 MT-ND3 ENSG00000198840 ENSP00000355206 NU3M_HUMAN P03897 4537 YP_003024033.1
4 MT-ND4 ENSG00000198886 ENSP00000354961 NU4M_HUMAN P03905 4538 YP_003024031.1
5 MT-ND4L ENSG00000212907 ENSP00000354728 NU4LM_HUMAN P03901 4539 YP_003024034.1
6 MT-ND5 ENSG00000198786 ENSP00000354813 NU5M_HUMAN P03915 4540 YP_003024036.1
7 MT-ND6 ENSG00000198695 ENSP00000354665 NU6M_HUMAN P03923 4541 YP_003024037.1
8 MT-ATP6 ENSG00000198899 ENSP00000354632 ATP6_HUMAN P00846 4508 YP_003024031.1
9 MT-ATP8 ENSG00000228253 ENSP00000355265 ATP8_HUMAN P03928 4509 YP_003024030.1
10 MT-CO1 ENSG00000198804 ENSP00000354499 COX1_HUMAN P00395 4512 YP_003024028.1
11 MT-CO2 ENSG00000198712 ENSP00000354876 COX2_HUMAN P00403 4513 YP_003024029.1
12 MT-CO3 ENSG00000198938 ENSP00000354982 COX3_HUMAN P00414 4514 YP_003024032.1
13 MT-CYB ENSG00000198727 ENSP00000354554 CYB_HUMAN P00156 4519 YP_003024038.1

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Main annotation databases

The putative effect of missense mutations within the 13 mitochondrially-encoded proteins was calculated by the following missense pathogenicity predictors:

  1. PolyPhen2 (ver. 2.2.2)
  2. SIFT (ver. 5.0.3)
  3. FatHmm (ver. 2.2, "weighted" and "unweighted" setting)
  4. MutationAssessor (ver. 2.0)
  5. PROVEAN (ver. 1.3)
  6. EFIN (accessed on May 2015)
  7. CADD (ver. 1.2)
  8. VEST (accessed through the CRAVAT webserver on June 2015)
  9. PANTHER (accessed through the Meta-SNP webserver on July 2015)
  10. PhD-SNP (accessed through the Meta-SNP webserver on July 2015)
  11. SNAP (accessed through the Meta-SNP webserver on July 2015)
  12. [NEW] MutationTaster ver. 2 (accessed on December 2016)
  13. [NEW] SNPdryad (accessed on December 2016)

Secondary annotation tools

Mutations were also annotated by these meta-predictors:

  1. CAROL (accessed on November 2014)
  2. Condel (accessed on November 2014)
  3. COVEC (vers. 0.4)
  4. Meta-SNP (accessed on July 2015)
  5. APOGEE (ver. 1.0)

Predictions can be obtained from the following web URLs:

  • PolyPhen2 - http://genetics.bwh.harvard.edu/pph2
  • SIFT - http://sift.bii.a-star.edu.sg
  • FatHmm - http://fathmm.biocompute.org.uk
  • PROVEAN - http://provean.jcvi.org
  • MutationAssessor - http://mutationassessor.org
  • EFIN - http://paed.hku.hk/efin
  • CADD - http://cadd.gs.washington.edu
  • VEST, CHASM - http://www.cravat.us
  • Meta-SNP, PANTHER, PhD-SNP, SNAP - http://snps.biofold.org/meta-snp
  • COVEC - http://sourceforge.net/projects/covec
  • CAROL - http://www.sanger.ac.uk/science/tools/carol
  • Condel - http://bg.upf.edu/fannsdb
  • MToolBox - https://github.com/mitoNGS/MToolBox/blob/master/MToolBox/data/patho_table.txt
  • [NEW] MutationTaster - http://www.mutationtaster.org
  • [NEW] SNPdryad - http://snps.ccbr.utoronto.ca:8080/SNPdryad/

Extra annotations

Additional annotations were retrieved from:
  • [UPDATE] Mitomap (accessed on December 2016)
  • [UPDATE] dbSNP (ver. 149)
  • [NEW] ClinVar (ver. 149)
  • PhyloP and PhastCons - evolutionary conservation indices (UCSC Gene Tables, group: Comparative Genomics; track: Conservation; tables: phyloP100wayAll and PhastCons100way) (UCSC accessed on May 2015)
  • SiteVar - human mtDNA site-specific variability (Hmtdb, Spring 2013)
  • [UPDATE] COSMIC - somatic variants (ver. 79)
  • MISTIC Mutual Information scores (accessed on May 2015)
  • CHASM (accessed through the CRAVAT webserver on June 2015)
  • TransFIC (accessed on May 2015)

Considered known pathogenic mutations:

Position Ref/Alt nt Gene AA position Ref/Alt aa dbSNP id dnSNP status Mitomap status Mitomap disease
Position Ref/Alt nt Gene AA position Ref/Alt aa dbSNP id dnSNP status Mitomap status Mitomap disease
15579 A/G MT-CYB 278 Y/C rs207460002 Pathogenic Confirmed Multisystem Disorder, EXIT
15615 G/A MT-CYB 290 G/D rs207459997 Pathogenic Reported EXIT / Antimycin resistance
15635 T/C MT-CYB 297 S/P NA NA Reported Polyvisceral failure
15662 A/G MT-CYB 306 I/V rs3094280 NA Reported Complex mitochondriopathy-associated
15674 T/C MT-CYB 310 S/P NA NA Reported LHON
15693 T/C MT-CYB 316 M/T rs200975632 NA Reported Possibly LVNC cardiomyopathy-associated
15699 G/C MT-CYB 318 R/P NA NA Reported Muscle Weakness SNHL and Migraine
9016 A/G MT-ATP6 164 I/V NA NA Reported LHON
15758 A/G MT-CYB 338 I/V rs527236193 Likely pathogenic NA NA
15762 G/A MT-CYB 339 G/E NA NA Reported MM
15812 G/A MT-CYB 356 V/M rs200336777 Pathogenic Reported / Secondary LHON
15884 G/A MT-CYB 380 A/T rs527236195 Likely pathogenic NA NA
3310 C/T MT-ND1 2 P/S NA NA Reported Diabetes / HCM
3340 C/T MT-ND1 12 P/S NA NA Reported Encephaloneuromyopathy
9035 T/C MT-ATP6 170 L/P NA NA Reported Ataxia syndromes
3376 G/A MT-ND1 24 E/K rs397515612 Pathogenic Cfrm LHON MELAS overlap
3380 G/A MT-ND1 25 R/Q NA NA Reported MELAS
3388 C/A MT-ND1 28 L/M rs387906730 Pathogenic Reported Materally Inherited Nonsyndromic Deafness
3394 T/C MT-ND1 30 Y/H rs41460449 Pathogenic NA NA
3395 A/G MT-ND1 30 Y/C NA NA Reported HCM with hearing loss
3397 A/G MT-ND1 31 M/V rs199476120 Pathogenic Reported ADPD / Possibly LVNC-cardiomyopathy associated
3398 T/C MT-ND1 31 M/T rs201212638 NA Reported DMDF+HCM / GDM / possibly LVNC cardiomyopathy-associated
3399 A/T MT-ND1 31 M/I rs386828905 NA Reported Gestational Diabetes (GDM)
3418 A/G MT-ND1 38 N/D NA NA Reported AMegL
3421 G/A MT-ND1 39 V/I NA NA Reported MIDD
3460 G/A MT-ND1 52 A/T rs199476118 Pathogenic Cfrm LHON
3472 T/C MT-ND1 56 F/L NA NA Reported LHON
3481 G/A MT-ND1 59 E/K rs587776433 Pathogenic Reported MELAS
9055 G/A MT-ATP6 177 A/T rs193303045 NA Reported PD protective factor
9058 A/G MT-ATP6 178 T/A NA NA Reported Possibly LVNC cardiomyopathy-associated
3635 G/A MT-ND1 110 S/N rs397515507 Pathogenic Cfrm LHON
3644 T/C MT-ND1 113 V/A NA NA Reported BD-associated
3688 G/A MT-ND1 128 A/T NA NA Reported Leigh Syndrome
3697 G/A MT-ND1 131 G/S rs199476122 Pathogenic Cfrm MELAS / LS / LDYT
3700 G/A MT-ND1 132 A/T rs397515508 Pathogenic Cfrm LHON
9071 C/T MT-ATP6 182 S/L NA NA Reported Potentially functional variant cosegregating with LHON3635A
3733 G/C MT-ND1 143 E/Q NA NA Reported LHON
3733 G/A MT-ND1 143 E/K rs199476125 Pathogenic Cfrm LHON
3736 G/A MT-ND1 144 V/I rs201513497 NA Reported LHON
3745 G/A MT-ND1 147 A/T NA NA Reported Possible adaptive high altitude variant
3796 A/G MT-ND1 164 T/A rs28357970 Pathogenic Reported Adult-Onset Dystonia
3833 T/A MT-ND1 176 L/Q NA NA Reported PEG
3866 T/C MT-ND1 187 I/T rs200479541 NA Reported LHON +limb claudication
3890 G/A MT-ND1 195 R/Q rs587776434 Pathogenic Cfrm Progressive encephalomyopathy / LS / optic atrophy
3928 G/C MT-ND1 208 V/L rs587776442 Pathogenic NA NA
3946 G/A MT-ND1 214 E/K rs199476123 Pathogenic Reported MELAS
3949 T/C MT-ND1 215 Y/H rs199476124 Pathogenic Reported MELAS
3959 G/A MT-ND1 218 G/D NA NA Reported MELAS
9098 T/C MT-ATP6 191 I/T rs201559119 NA Reported Predisposition to anti-retroviral mito disease
3995 A/G MT-ND1 230 N/S NA NA Reported MELAS
9101 T/C MT-ATP6 192 I/T rs199476134 Pathogenic Reported LHON
4025 C/T MT-ND1 240 T/M rs397515509 Pathogenic NA NA
4132 G/A MT-ND1 276 A/T NA NA Reported NAION-associated
4136 A/G MT-ND1 277 Y/C rs199476121 Pathogenic NA NA
4142 G/A MT-ND1 279 R/Q NA NA Reported Developmental delay, seizure, hypotonia
4160 T/C MT-ND1 285 L/P rs199476119 Pathogenic Reported LHON
4171 C/A MT-ND1 289 L/M rs28616230 Pathogenic Cfrm LHON
9139 G/A MT-ATP6 205 A/T NA NA Reported - possibly synergistic LHON
4633 C/G MT-ND2 55 A/G NA NA Reported LHON candidate
4640 C/A MT-ND2 57 I/M rs387906426 Pathogenic Reported LHON
4648 T/C MT-ND2 60 F/S NA NA Reported PEG
4659 G/A MT-ND2 64 A/T NA NA Reported possible PD risk factor
4681 T/C MT-ND2 71 L/P rs267606889 Pathogenic Reported Leigh Syndrome
4833 A/G MT-ND2 122 T/A NA NA Reported; haplogroup G marker Diabetes helper mutation; AD, PD
4852 T/A MT-ND2 128 L/Q NA NA Reported LHON
4917 A/G MT-ND2 150 N/D rs28357980 Uncertain significance Reported; haplogroup T marker LHON / Insulin Resistance / AMD / NRTI-PN
9176 T/C MT-ATP6 217 L/P rs199476135 Pathogenic Cfrm FBSN / Leigh Disease
9176 T/G MT-ATP6 217 L/R rs199476135 Pathogenic Cfrm Leigh Disease / Spastic Paraplegia
9185 T/C MT-ATP6 220 L/P rs199476138 Pathogenic Cfrm Leigh Disease / Ataxia syndromes / NARP-like disease
9191 T/C MT-ATP6 222 L/P rs386829069 Pathogenic Reported Leigh Disease
5178 C/A MT-ND2 237 L/M rs28357984 NA Reported; haplogroup D marker Longevity; Extraversion MI / AMS protection; blood iron metabolism
5244 G/A MT-ND2 259 G/S rs199476115 Pathogenic Reported LHON
8381 A/G MT-ATP8 6 T/A NA NA Reported MIDD / LVNC cardiomyopathy-assoc.
5452 C/T MT-ND2 328 T/M NA NA Reported Progressive Encephalomyopathy
5460 G/T MT-ND2 331 A/S NA NA Reported AD
10086 A/G MT-ND3 10 N/D rs28358274 NA Reported Hypertensive end-stage renal disease
8393 C/T MT-ATP8 10 P/S rs121434446 risk factor Reported Reversible brain pseudoatrophy
10134 C/A MT-ND3 26 Q/K rs587780529 Pathogenic NA NA
10158 T/C MT-ND3 34 S/P rs199476117 Pathogenic Cfrm Leigh Disease
10191 T/C MT-ND3 45 S/P rs267606890 Pathogenic Cfrm Leigh Disease / Leigh-like Disease / ESOC
8403 T/C MT-ATP8 13 I/T NA NA Reported Episodic weakness and progressive neuropathy
10197 G/A MT-ND3 47 A/T rs267606891 Pathogenic Cfrm Leigh Disease / Dystonia / Stroke / LDYT
10237 T/C MT-ND3 60 I/T rs193302927 Pathogenic Reported LHON
10254 G/A MT-ND3 66 D/N rs587776438 Pathogenic Reported Leigh Disease
8411 A/G MT-ATP8 16 M/V NA NA Reported Severe mitochondrial disorder
8414 C/T MT-ATP8 17 L/F rs28358884 NA Reported Longevity
10543 A/G MT-ND4L 25 H/R NA NA Reported LHON
10563 T/C MT-ND4L 32 C/R rs267606892 Pathogenic NA NA
10591 T/G MT-ND4L 41 F/C NA NA Reported LHON
10663 T/C MT-ND4L 65 V/A rs193302933 Pathogenic Cfrm LHON
8481 C/T MT-ATP8 39 P/L NA NA Reported Tetralogy of Fallot patient
11084 A/G MT-ND4 109 T/A rs199476113 Pathogenic NA NA
11232 T/C MT-ND4 158 L/P NA NA Reported CPEO
11253 T/C MT-ND4 165 I/T rs200145866 Pathogenic Reported LHON; PD
11375 A/C MT-ND4 206 K/Q NA NA Reported found in 1 sCJD patient
8519 G/A MT-ATP8 52 E/K rs878853091 Likely benign Reported Susceptibility to bullous pemphigoid
8528 T/C MT-ATP8 55 W/R rs387906422 Pathogenic NA NA
11696 G/A MT-ND4 313 V/I rs200873900 Pathogenic Reported - possibly synergistic LHON / LDYT / DEAF / hypertension helper mut.
11777 C/A MT-ND4 340 R/S rs28384199 Pathogenic Cfrm Leigh Disease
11778 G/A MT-ND4 340 R/H rs199476112 Pathogenic Cfrm LHON / Progressive Dystonia
11874 C/A MT-ND4 372 T/N NA NA Reported LHON
11919 C/T MT-ND4 387 S/F NA NA Reported Thyroid Cancer Cell Line
11984 T/C MT-ND4 409 Y/H rs200911567 Pathogenic NA NA
5911 C/T MT-CO1 3 A/V NA NA Reported Prostate Cancer
12026 A/G MT-ND4 423 I/V rs202136725 NA Reported DM
5913 G/A MT-CO1 4 D/N rs201617272 NA Reported Prostate Cancer / hypertension
12027 T/C MT-ND4 423 I/T NA NA Reported SZ-associated
12338 T/C MT-ND5 1 M/T rs201863060 Pathogenic NA NA
12361 A/G MT-ND5 9 T/A rs3134561 NA Reported Nonalcoholic fatty liver disease
12397 A/G MT-ND5 21 T/A rs200890363 risk factor Reported PD, early onset
5935 A/G MT-CO1 11 N/S NA NA Reported Prostate Cancer
12631 T/A MT-ND5 99 S/T NA NA Reported found in 2 sCJD patients
12634 A/G MT-ND5 100 I/V NA NA Reported Thyroid Cancer Cell Line
12706 T/C MT-ND5 124 F/L rs267606893 Pathogenic Cfrm Leigh Disease
12770 A/G MT-ND5 145 E/G rs267606894 Pathogenic Reported MELAS
12782 T/G MT-ND5 149 I/S NA NA Reported LHON
12811 T/C MT-ND5 159 Y/H rs199974018 Pathogenic Reported Possible LHON factor
5973 G/A MT-CO1 24 A/T NA NA Reported Prostate Cancer
12848 C/T MT-ND5 171 A/V rs267606899 Pathogenic Reported LHON
13042 G/A MT-ND5 236 A/T rs267606898 Pathogenic Reported Optic neuropathy / retinopathy / LD
13045 A/C MT-ND5 237 M/L rs267606895 Pathogenic Reported MELAS / LHON / Leigh overlap syndrome
13051 G/A MT-ND5 239 G/S NA NA Cfrm LHON
13063 G/A MT-ND5 243 V/I NA NA Reported Adult-onset Encephalopathy / Ataxia
13084 A/T MT-ND5 250 S/C rs267606896 Pathogenic Reported MELAS / Leigh Disease
13094 T/C MT-ND5 253 V/A NA NA Reported Ataxia+PEO / MELAS, LD, myoclonus, fatigue
13135 G/A MT-ND5 267 A/T rs200044200 NA Reported possible HCM susceptibility
13271 T/C MT-ND5 312 L/P NA NA Reported Exercise intolerance (EXIT)
13379 A/C MT-ND5 348 H/P NA NA Reported LHON
13511 A/T MT-ND5 392 K/M NA NA Reported Leigh-like syndrome
13513 G/A MT-ND5 393 D/N rs267606897 Pathogenic Cfrm Leigh Disease / MELAS / LHON-MELAS Overlap Syndrome
13514 A/G MT-ND5 393 D/G rs587776440 Pathogenic Cfrm Leigh Disease / MELAS
13528 A/G MT-ND5 398 T/A rs55882959 NA Reported LHON-like, LHON, MELAS
13580 C/G MT-ND5 415 A/G NA NA Reported Thyroid Cancer
13637 A/G MT-ND5 434 Q/R rs200855215 Pathogenic Reported Possible LHON factor
13730 G/A MT-ND5 465 G/E rs387906425 Pathogenic Reported LHON
13831 C/A MT-ND5 499 L/M NA NA Reported Thyroid Cancer Cell Line
6081 G/A MT-CO1 60 A/T NA NA Reported Prostate Cancer
13967 C/T MT-ND5 544 T/M NA NA Reported Possible LHON factor
14063 T/C MT-ND5 576 I/T NA NA Reported Potentially functional variant cosegregating with LHON3635A
14091 A/T MT-ND5 585 K/N NA NA Reported Developmental delay, seizure, hearing loss, diabetes
14279 G/A MT-ND6 132 S/L rs869025187 Pathogenic Reported LHON
14319 T/C MT-ND6 119 N/D rs199476110 risk factor Reported PD, early onset
14325 T/C MT-ND6 117 N/D rs397515505 Pathogenic Reported LHON
14340 C/T MT-ND6 112 V/M NA NA Reported SNHL
14430 A/G MT-ND6 82 W/R NA NA Reported Thyroid Cancer
14439 G/A MT-ND6 79 P/S NA NA Reported Mitochondrial Respiratory Chain Disorder
14453 G/A MT-ND6 74 A/V rs199476107 Pathogenic Reported MELAS
14459 G/A MT-ND6 72 A/V rs199476105 Pathogenic Cfrm LDYT / Leigh Disease
14482 C/A MT-ND6 64 M/I rs199476108 Pathogenic Cfrm LHON
14482 C/G MT-ND6 64 M/I rs199476108 Pathogenic Cfrm LHON
14484 T/C MT-ND6 64 M/V rs199476104 Pathogenic; Likely pathogenic Cfrm LHON
14487 T/C MT-ND6 63 M/V rs199476109 Pathogenic Cfrm Dystonia / Leigh Disease / Ataxia / Ptosis / Epilepsy
14495 A/G MT-ND6 60 L/S rs199476106 Pathogenic Cfrm LHON
14498 T/C MT-ND6 59 Y/C rs869025186 Pathogenic Reported LHON
14568 C/T MT-ND6 36 G/S rs397515506 Pathogenic Cfrm LHON
14577 T/C MT-ND6 33 I/V rs386829219 NA Reported MIDM
14596 A/T MT-ND6 26 I/M rs387906424 Pathogenic Reported LHON
14597 A/G MT-ND6 26 I/T rs797045055 Likely pathogenic; Likely pathogenic NA NA
14600 G/A MT-ND6 25 P/L NA NA Reported Leigh Disease w/optic atrophy
6150 G/A MT-CO1 83 V/I NA NA Reported Prostate Cancer / enriched in POAG cohort
6253 T/C MT-CO1 117 M/T rs200165736 NA Reported Prostate Cancer / enriched in POAG cohort
6261 G/A MT-CO1 120 A/T rs201262114 Likely benign Reported Prostate Cancer / LHON
6267 G/A MT-CO1 122 A/T rs202216551 NA Reported Prostate Cancer
6277 G/A MT-CO1 125 G/D rs281865417 Pathogenic NA NA
6285 G/A MT-CO1 128 V/I NA NA Reported Prostate Cancer
6328 C/T MT-CO1 142 S/F rs267606883 Pathogenic Reported EXIT (Exercise Intolerance)
6340 C/T MT-CO1 146 T/I NA NA Reported Prostate Cancer
8668 T/C MT-ATP6 48 W/R NA NA Reported LHON
6480 G/A MT-CO1 193 V/I rs199476128 Pathogenic Reported Prostate Cancer / enriched in POAG cohort
6489 C/A MT-CO1 196 L/I rs28461189 Pathogenic Reported Therapy-Resistant Epilepsy
6597 C/A MT-CO1 232 Q/K NA NA Reported MELAS-like syndrome
6663 A/G MT-CO1 254 I/V rs200784106 NA Reported Prostate Cancer
6721 T/C MT-CO1 273 M/T rs199476127 Pathogenic Reported Acquired Idiopathic Sideroblastic Anemia
6742 T/C MT-CO1 280 I/T rs199476126 Pathogenic Reported Acquired Idiopathic Sideroblastic Anemia
8528 T/C MT-ATP6 1 M/T rs387906422 Pathogenic NA NA
6955 G/A MT-CO1 351 G/D NA NA Reported Mild EXIT and MR
7023 G/A MT-CO1 374 V/M NA NA Reported MELAS-like syndrome
7041 G/A MT-CO1 380 V/I NA NA Reported Prostate Cancer
7080 T/C MT-CO1 393 F/L NA NA Reported Prostate Cancer
7083 A/G MT-CO1 394 I/V NA NA Reported Prostate Cancer
8741 T/G MT-ATP6 72 L/R NA NA Reported MILS protective factor
7158 A/G MT-CO1 419 I/V NA NA Reported Prostate Cancer
7275 T/C MT-CO1 458 S/P rs267606884 Pathogenic NA NA
7305 A/C MT-CO1 468 M/L NA NA Reported Prostate Cancer
7587 T/C MT-CO2 1 M/T rs199474825 Pathogenic Reported Mitochondrial Encephalomyopathy
7598 G/A MT-CO2 5 A/T NA NA Reported Possible LHON helper variant
7623 C/T MT-CO2 13 T/I NA NA Reported LHON
7637 G/A MT-CO2 18 E/K NA NA Reported PD risk factor
7671 T/A MT-CO2 29 M/K rs199474827 Pathogenic Reported MM
7697 G/A MT-CO2 38 V/I NA NA Reported Possible HCM susceptibility
8794 C/T MT-ATP6 90 H/Y rs2298007 NA Reported Exercise Endurance / Coronary Atherosclerosis risk
8795 A/G MT-ATP6 90 H/R NA NA Reported MILS protective factor
7859 G/A MT-CO2 92 D/N rs373105186 NA Reported Progressive Encephalomyopathy
7877 A/C MT-CO2 98 K/Q NA NA Reported PEG glaucoma
7989 T/C MT-CO2 135 L/P NA NA Reported Rhabdomyolysis
8009 G/A MT-CO2 142 V/M rs199474826 Pathogenic NA NA
8010 T/C MT-CO2 142 V/A NA NA Reported Developmental delay, ataxia, seizure, hypotonia, lactic acidosis
8021 A/G MT-CO2 146 I/V NA NA Reported Asthenozoospermia
8078 G/A MT-CO2 165 V/I NA NA Reported DEAF
8108 A/G MT-CO2 175 I/V NA NA Reported SNHL
8836 A/G MT-ATP6 104 M/V NA NA Reported LHON
8839 G/C MT-ATP6 105 A/P rs369202065 Pathogenic NA NA
9267 G/C MT-CO3 21 A/P NA NA Reported MIDD
8851 T/C MT-ATP6 109 W/R rs199476136 Pathogenic Reported BSN
9387 G/A MT-CO3 61 V/M NA NA Reported Asthenozoospermia
9438 G/A MT-CO3 78 G/S rs267606611 Pathogenic NA NA
9478 T/C MT-CO3 91 V/A rs587776437 Pathogenic Reported Leigh Disease
9544 G/A MT-CO3 113 G/E NA NA Reported Sporadic bilateral optic neuropathy
9660 A/C MT-CO3 152 M/L NA NA Reported LHON
8890 A/G MT-ATP6 122 K/E NA NA Reported Juevnile-onset metabolic syndrome
9738 G/T MT-CO3 178 A/S NA NA Reported LHON
9789 T/C MT-CO3 195 S/P NA NA Reported Myopathy
9804 G/A MT-CO3 200 A/T rs200613617 Pathogenic Reported LHON
9861 T/C MT-CO3 219 F/L rs878853060 Likely benign Reported AD
9957 T/C MT-CO3 251 F/L NA NA Reported PEM / MELAS / NAION
9972 A/C MT-CO3 256 I/L NA NA Reported EXIT & APS2 - possible link
14753 C/T MT-CYB 3 P/S rs527236162 Likely pathogenic NA NA
14766 C/T MT-CYB 7 T/I rs527236041 Likely pathogenic NA NA
14784 T/C MT-CYB 13 L/S rs527236163 Likely pathogenic NA NA
14831 G/A MT-CYB 29 A/T rs199795644 Pathogenic Reported LHON
14841 A/G MT-CYB 32 N/S NA NA Reported LHON helper mut.
14846 G/A MT-CYB 34 G/S rs207459998 Pathogenic Reported EXIT
14849 T/C MT-CYB 35 S/P rs207460004 Pathogenic Confirmed EXIT / Septo-Optic Dysplasia
14864 T/C MT-CYB 40 C/R NA NA Confirmed MELAS
8932 C/T MT-ATP6 136 P/S rs878853013 Likely benign Reported Prostate Cancer / Neuromuscular disorder
14891 C/G MT-CYB 49 L/V rs386419981 Likely pathogenic NA NA
14985 G/A MT-CYB 80 R/H rs207459995 Pathogenic NA NA
15024 G/A MT-CYB 93 C/Y NA NA Reported Possible DEAF modifier
8950 G/A MT-ATP6 142 V/I NA NA Reported LDYT
15077 G/A MT-CYB 111 E/K rs201943501 NA Reported DEAF
15092 G/A MT-CYB 116 G/S NA NA Reported MELAS
15098 A/G MT-CYB 118 I/V rs527236172 Likely pathogenic NA NA
15197 T/C MT-CYB 151 S/P rs207460001 Pathogenic Reported EXIT
15209 T/C MT-CYB 155 Y/H NA NA Reported Prader-Willi syndrome
15237 T/C MT-CYB 164 I/T NA NA Reported Potentially functional variant cosegregating with LHON3635A
15243 G/A MT-CYB 166 G/E NA NA Reported HCM
8969 G/A MT-ATP6 148 S/N rs794726857 Pathogenic Reported Mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA)
15287 T/C MT-CYB 181 F/L rs527236044 Likely pathogenic NA NA
15314 G/A MT-CYB 190 A/T rs527236176 Likely pathogenic NA NA
15323 G/A MT-CYB 193 A/T rs527236177 Likely pathogenic NA NA
15326 A/G MT-CYB 194 T/A rs2853508 Likely pathogenic NA NA
15349 C/A MT-CYB 201 H/Q rs527236201 Likely pathogenic NA NA
15363 A/G MT-CYB 206 N/S rs527236182 Likely pathogenic NA NA
15395 A/G MT-CYB 217 K/E NA NA Reported Possible LHON factor
15431 G/A MT-CYB 229 A/T rs527236208 Likely pathogenic NA NA
15452 C/A MT-CYB 236 L/I rs193302994 Likely pathogenic NA NA
15453 T/C MT-CYB 236 L/P rs527236184 Likely pathogenic Reported Isolated complex III deficiency
15458 T/C MT-CYB 238 S/P rs527236185 Likely pathogenic NA NA
15459 C/T MT-CYB 238 S/F rs527236186 Likely pathogenic NA NA
8989 G/C MT-ATP6 155 A/P rs587776444 Pathogenic NA NA
15497 G/A MT-CYB 251 G/S rs199951903 risk factor Reported EXIT / Obesity
15498 G/A MT-CYB 251 G/D rs207460003 Pathogenic Reported HiCM / WPW, DEAF
8993 T/G MT-ATP6 156 L/R rs199476133 Pathogenic Cfrm NARP / Leigh Disease / MILS / other
8993 T/C MT-ATP6 156 L/P rs199476133 Pathogenic Cfrm NARP / Leigh Disease / MILS / other

Reported  means that one or more papers have hypothesized a pathologic role for that mutation;

Reported – haplogroup indicates that the considered mutation characterizes also a specific human mtDNA haplogroup;

Confirmed indicates that the mutation is disease-causing.

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[NEW] APOGEE

APOGEE is a LMT-based consensus classifier.
LMT (Logistic Model Tree) is a machine learning technique which consists of a combination of decision trees and logistic regressions at the leaves. The model is evaluated on the basis of some predictor variables that can be used for making decisions in the tree construction and selected for logistic models.
The difference between decision tree and LMT is that the former classifies all the instances belonging to a leaf with the class having the highest frequency in the leaf. While LMT constructs a logistic model for classifying the instances in the same leaf by giving, to each instance, the probability of belonging to a class.

APOGEE handles two pathogenicity classes: neutral and pathogenic. Mutations are considered as instances of the following predictors:

  • PhyloP 100V
  • PhastCons 100V
  • PolyPhen2 (HumDiv dataset)
  • SIFT
  • FatHmm (weighted version)
  • PROVEAN
  • Mutation Assessor
  • EFIN (SwissProt dataset)
  • EFIN (HumDiv dataset)
  • CADD Phred
  • PANTHER
  • PhD-SNP
  • SNAP

Once defined the classification function, we implemented and tested a bootstrap strategy, which randomly selected 70% of the pathogenic mutations and considered the same number of neutral mutations. In brief, for 100 iterations, we run this algorithm:

  • Sampling the training set, as described above;
  • Estimating the LMT;
  • Predicting the pathogenicity of all the mutations stored in the database.
Each iteration gave an estimate of pathogenicity for each variant. These were summarized by calculating the probability mean for each variant. A variant was deemed harmful if the mean of the probabilities of being harmful calculated on 100 runs resulted > 0.5. Compared to a single run of LMT, the bootstrap strategy implies a loss of generalization of the resulting model.

The LMT models generated during the 100 iterations can be downloaded here.

Comparison of the performance of classification among meta-predictors

Method Accuracy Precision FDR MCC MCR
MetaSNP 0.54 0.29 0.71 0.09 45.83
CAROL 0.59 0.33 0.67 0.13 40.28
Condel 0.49 0.23 0.78 -0.08 51.16
COVERC WMV 0.59 0.33 0.67 0.12 41.27
[NEW] MToolBox DS 0.48 0.28 0.72 0.06 51.62
[NEW] APOGEE bootstrap 0.84 0.73 0.27 0.59 15.97

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Programmatic access to data

Variants can be searched by a new RESTfull interface, either directly in your browser or by curl.
The output is formatted in JSON. The empty result set is a string: {"variants": null}.

  1. curl mitimpact.css-mendel.it/api/v2.0/genomic_position/3307
  2. [range query] curl mitimpact.css-mendel.it/api/v2.0/genomic_position/3307-3309
  3. curl mitimpact.css-mendel.it/api/v2.0/dbsnp/rs3020563
  4. [multiple query] curl mitimpact.css-mendel.it/api/v2.0/dbsnp/rs3020563,rs28520706,rs1041870
  5. curl mitimpact.css-mendel.it/api/v2.0/protein_position?pos=20&id=MT-ATP6
  6. [multiple query] curl mitimpact.css-mendel.it/api/v2.0/protein_position?pos=10&id=ENSG00000198840,P00414
  7. [multiple range query] curl mitimpact.css-mendel.it/api/v2.0/protein_position?pos=10-12&id=ENSG00000198840,P00414
  8. [multiple query] curl mitimpact.css-mendel.it/api/v2.0/protein_position?pos=10,11,13&id=ENSG00000198840,P00414
  9. [UPDATE] curl mitimpact.css-mendel.it/api/v2.0/pathogenicity?id=ID&min=9, where ID can be any gene or protein identifier in the table above. The parameter "min" specifies the minimum number of pathogenic assessments that a variant in the result set must have. This function queries: PolyPhen2, SIFT, FatHmm, FatHmmW, PROVEAN, MutationAssessor, EFIN_SP, EFIN_HD, CADD, PANTHER, PhD-SNP, SNAP and MutationTaster.
  10. curl mitimpact.css-mendel.it/api/v2.0/consensus_pathogenicity?id=ID&min=2, where ID can be any gene or protein identifier in the table above. The parameter "min" specifies the minimum number of pathogenic assessments that a variant in the result set must have. This function queries the meta-predictors: Meta-SNP, CAROL, Condel, COVEC WMV, MToolBox and APOGEE.

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