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. MutationTaster ver. 2 (accessed on December 2016)
  13. SNPdryad (accessed on December 2016)
  14. [NEW] DEOGEN (accessed on October 2017)

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
  • MutationTaster - http://www.mutationtaster.org
  • SNPdryad - http://snps.ccbr.utoronto.ca:8080/SNPdryad/

Extra annotations

Additional annotations were retrieved from:
  • [UPDATE] Mitomap (accessed on July 2017)
  • [UPDATE] dbSNP (ver. 150)
  • [UPDATE] ClinVar (accessed on 5 October 2017)
  • 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)
  • 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)
  • [NEW] Compensated Pathogenic Deviations

Considered known pathogenic mutations:

Position ref/alt nt Gene Gene AA position Ref/Alt aa dbSNP id dbSNP status MITOMAP phenotype MITOMAP status
Position ref/alt nt Gene Gene AA position Ref/Alt aa dbSNP id dbSNP status MITOMAP phenotype MITOMAP status
15572 T/C MT-CYB 276 F/L rs207459996 Pathogenic . .
15579 A/G MT-CYB 278 Y/C rs207460002 Pathogenic Multisystem Disorder, EXIT Confirmed
15615 G/A MT-CYB 290 G/D rs207459997 Pathogenic EXIT/Antimycin resistance Reported
15620 C/A MT-CYB 292 L/I . . Leigh Syndrome helper mut Reported
15635 T/C MT-CYB 297 S/P . . Polyvisceral failure Reported
15670 T/A MT-CYB 308 H/Q rs193302997 Likely pathogenic . .
15670 T/G MT-CYB 308 H/Q rs193302997 Likely pathogenic . .
15674 T/C MT-CYB 310 S/P . . LHON Reported
15699 G/C MT-CYB 318 R/P . . Muscle Weakness SNHL and Migraine Reported
9016 A/G MT-ATP6 164 I/V . . LHON Reported
15758 A/G MT-CYB 338 I/V rs527236193 Likely pathogenic . .
15762 G/A MT-CYB 339 G/E . . MM Reported
3308 T/A MT-ND1 1 M/K rs28358582 Pathogenic|Likely benign . .
3310 C/T MT-ND1 2 P/S . . Diabetes/HCM Reported
3340 C/T MT-ND1 12 P/S . . Encephaloneuromyopathy Reported
9035 T/C MT-ATP6 170 L/P . . Ataxia syndrome Reported
3376 G/A MT-ND1 24 E/K rs397515612 Pathogenic LHON MELAS overlap Cfrm
3380 G/A MT-ND1 25 R/Q . . MELAS Reported
3388 C/A MT-ND1 28 L/M rs387906730 Pathogenic Materally Inherited Nonsyndromic Deafness Reported
3395 A/G MT-ND1 30 Y/C . . HCM with hearing loss Reported
3397 A/G MT-ND1 31 M/V rs199476120 Pathogenic ADPD/PossiblyLVNC-cardiomyopathy associated Reported
3418 A/G MT-ND1 38 N/D . . AMegL Reported
3421 G/A MT-ND1 39 V/I . . MIDD Reported
3460 G/A MT-ND1 52 A/T rs199476118 Pathogenic LHON Cfrm
3472 T/C MT-ND1 56 F/L . . LHON Reported
3481 G/A MT-ND1 59 E/K rs587776433 Pathogenic Progressive Encephalomyopathy Reported
3488 T/C MT-ND1 61 L/P . . LHON (putative) Reported
3551 C/T MT-ND1 82 A/V . . LHON (putative) Reported
9058 A/G MT-ATP6 178 T/A . . Possibly LVNC cardiomyopathy-associated Reported
3632 C/T MT-ND1 109 S/F . . LHON (putative) Reported
3635 G/A MT-ND1 110 S/N rs397515507 Pathogenic LHON Cfrm
3688 G/A MT-ND1 128 A/T . . Leigh Syndrome Reported
3697 G/A MT-ND1 131 G/S rs199476122 Pathogenic MELAS/LS/LDYT Cfrm
3700 G/A MT-ND1 132 A/T rs397515508 Pathogenic LHON Cfrm
9071 C/T MT-ATP6 182 S/L . . Potentially functional variant cosegregating with LHON 3635A Reported
3713 T/C MT-ND1 136 V/A . . LHON (putative) Reported
3733 G/C MT-ND1 143 E/Q . . LHON Reported
3733 G/A MT-ND1 143 E/K rs199476125 Pathogenic LHON Cfrm
3745 G/A MT-ND1 147 A/T . . Possible adaptive high altitude variant Reported
3769 C/G MT-ND1 155 L/V . . LHON (putative) Reported
3781 T/C MT-ND1 159 S/P . . LHON (putative) Reported
3833 T/A MT-ND1 176 L/Q . . PEG Reported
3890 G/A MT-ND1 195 R/Q rs587776434 Pathogenic Progressive encephalomyopathy/LS/optic atrophy Cfrm
3919 T/C MT-ND1 205 S/P . . LHON (putative) Reported
3928 G/C MT-ND1 208 V/L rs587776442 Pathogenic . .
3946 G/A MT-ND1 214 E/K rs199476123 Pathogenic MELAS Reported
3949 T/C MT-ND1 215 Y/H rs199476124 Pathogenic MELAS Reported
3958 G/A MT-ND1 218 G/S . . LHON (putative) Reported
3959 G/A MT-ND1 218 G/D . . MELAS Reported
3995 A/G MT-ND1 230 N/S . . MELAS Reported
9101 T/C MT-ATP6 192 I/T rs199476134 Pathogenic LHON Reported
4025 C/A MT-ND1 240 T/K rs397515509 Pathogenic . .
4025 C/T MT-ND1 240 T/M rs397515509 Pathogenic . .
4081 T/C MT-ND1 259 F/L . . LHON (putative) Reported
4123 A/T MT-ND1 273 I/F . . LHON (putative) Reported
4142 G/A MT-ND1 279 R/Q . . Developmental delay,seizure,hypotonia Reported
4160 T/C MT-ND1 285 L/P rs199476119 Pathogenic LHON Reported
4163 T/C MT-ND1 286 M/T . . LHON (putative) Reported
4171 C/A MT-ND1 289 L/M rs28616230 Pathogenic LHON Cfrm
4633 C/G MT-ND2 55 A/G . . LHON candidate Reported
4640 C/A MT-ND2 57 I/M rs387906426 Pathogenic LHON Reported
4648 T/C MT-ND2 60 F/S . . PEG Reported
4659 G/A MT-ND2 64 A/T . . Possible PD risk factor Reported
4681 T/C MT-ND2 71 L/P rs267606889 Pathogenic Leigh Syndrome Reported
4833 A/G MT-ND2 122 T/A . . Diabetes helper mutation,AD,PD Reported,haplogroup G marker
4852 T/A MT-ND2 128 L/Q . . LHON Reported
9166 T/C MT-ATP6 214 F/L rs1057516063 Likely pathogenic . .
9176 T/C MT-ATP6 217 L/P rs199476135 Pathogenic FBSN/Leigh Disease Cfrm
9176 T/G MT-ATP6 217 L/R rs199476135 Pathogenic Leigh Disease/Spastic Paraplegia Cfrm
9185 T/C MT-ATP6 220 L/P rs199476138 Pathogenic Leigh Disease/Ataxia syndromes/NARP-like disease Cfrm
9191 T/C MT-ATP6 222 L/P rs386829069 Pathogenic Leigh Disease Reported
5244 G/A MT-ND2 259 G/S rs199476115 Pathogenic LHON Reported
8381 A/G MT-ATP8 6 T/A . . MIDD/LVNC cardiomyopathy-assoc. Reported
5452 C/T MT-ND2 328 T/M . . Progressive Encephalomyopathy Reported
5460 G/T MT-ND2 331 A/S . . AD Reported
10134 C/A MT-ND3 26 Q/K rs587780529 Pathogenic . .
10158 T/C MT-ND3 34 S/P rs199476117 Pathogenic Leigh Disease Cfrm
10191 T/C MT-ND3 45 S/P rs267606890 Pathogenic Leigh Disease/Leigh-like Disease/ESOC Cfrm
8403 T/C MT-ATP8 13 I/T . . Episodic weakness and progressive neuropathy Reported
10197 G/A MT-ND3 47 A/T rs267606891 Pathogenic Leigh Disease/Dystonia/Stroke/LDYT Cfrm
10237 T/C MT-ND3 60 I/T rs193302927 Pathogenic LHON Reported
10254 G/A MT-ND3 66 D/N rs587776438 Pathogenic Leigh Disease Reported
8411 A/G MT-ATP8 16 M/V . . Severe mitochondrial disorder Reported
8418 T/C MT-ATP8 18 L/P rs1057516062 Likely pathogenic . .
10543 A/G MT-ND4L 25 H/R . . LHON Reported
10563 T/C MT-ND4L 32 C/R rs267606892 Pathogenic . .
10591 T/G MT-ND4L 41 F/C . . LHON Reported
10663 T/C MT-ND4L 65 V/A rs193302933 Pathogenic LHON Cfrm
8481 C/T MT-ATP8 39 P/L . . Tetralogy of Fallot patient Reported
11232 T/C MT-ND4 158 L/P . . CPEO Reported
11240 C/T MT-ND4 161 L/F . . Leigh Syndrome Reported
11253 T/C MT-ND4 165 I/T rs200145866 Pathogenic LHON, PD Reported
11375 A/C MT-ND4 206 K/Q . . found in 1 sCJD patient Reported
8528 T/C MT-ATP8 55 W/R rs387906422 Pathogenic Infantile cardiomyopathy Confirmed
11777 C/G MT-ND4 340 R/G rs28384199 Pathogenic . .
11777 C/A MT-ND4 340 R/S rs28384199 Pathogenic Leigh Disease Cfrm
11778 G/A MT-ND4 340 R/H rs199476112 Pathogenic LHON/Progressive Dystonia Cfrm
8558 C/T MT-ATP8 65 P/S . . Possibly LVNC cardiomyopathy-associated Reported
8561 C/G MT-ATP8 66 P/A . . Ataxia neuropathy,DM,SNHL and hypogonadism Reported
11874 C/A MT-ND4 372 T/N . . LHON Reported
11919 C/T MT-ND4 387 S/F . . Thyroid Cancer Cell Line Reported
11984 T/C MT-ND4 409 Y/H rs200911567 Pathogenic . .
12027 T/C MT-ND4 423 I/T . . SZ-associated Reported
5935 A/G MT-CO1 11 N/S . . Prostate Cancer Reported
12631 T/A MT-ND5 99 S/T . . found in 2 sCJD patients Reported
12634 A/G MT-ND5 100 I/V . . Thyroid Cancer Cell Line Reported
12706 T/C MT-ND5 124 F/L rs267606893 Pathogenic Leigh Disease Cfrm
12770 A/G MT-ND5 145 E/G rs267606894 Pathogenic MELAS Reported
12782 T/G MT-ND5 149 I/S . . LHON Reported
12811 T/C MT-ND5 159 Y/H rs199974018 Pathogenic Possible LHON factor Reported
5973 G/A MT-CO1 24 A/T . . Prostate Cancer Reported
12848 C/T MT-ND5 171 A/V rs267606899 Pathogenic LHON Reported
13042 G/A MT-ND5 236 A/T rs267606898 Pathogenic Optic neuropathy/retinopathy/LD Reported
13045 A/C MT-ND5 237 M/L rs267606895 Pathogenic MELAS/LHON/Leigh overlap syndrome Reported
13051 G/A MT-ND5 239 G/S . . LHON Cfrm
13063 G/A MT-ND5 243 V/I . . Adult-onset Encephalopathy/Ataxia Reported
13084 A/T MT-ND5 250 S/C rs267606896 Pathogenic MELAS/Leigh Disease Reported
13094 T/C MT-ND5 253 V/A . . Ataxia+PEO/MELAS,LD,myoclonus,fatigue Reported
13271 T/C MT-ND5 312 L/P . . Exercise intolerance(EXIT) Reported
13379 A/C MT-ND5 348 H/P . . LHON Reported
13511 A/T MT-ND5 392 K/M . . Leigh-likesyndrome Reported
13513 G/A MT-ND5 393 D/N rs267606897 Pathogenic Leigh Disease/MELAS/LHON-MELAS Overlap Syndrome Cfrm
13514 A/G MT-ND5 393 D/G rs587776440 Pathogenic LeighDisease/MELAS Cfrm
13580 C/G MT-ND5 415 A/G . . Thyroid Cancer Reported
13637 A/G MT-ND5 434 Q/R rs200855215 Pathogenic Possible LHON factor Reported
13730 G/A MT-ND5 465 G/E rs387906425 Pathogenic LHON Reported
13831 C/A MT-ND5 499 L/M . . Thyroid Cancer Cell Line Reported
6081 G/A MT-CO1 60 A/T . . Prostate Cancer Reported
13967 C/T MT-ND5 544 T/M . . Possible LHON factor Reported
14063 T/C MT-ND5 576 I/T . . Potentially functional variant cosegregating with LHON 3635A Reported
14091 A/T MT-ND5 585 K/N . . Developmental delay,seizure,hearing loss,diabetes Reported
14279 G/A MT-ND6 132 S/L rs869025187 Pathogenic LHON Reported
14325 T/C MT-ND6 117 N/D rs397515505 Pathogenic LHON Reported
14340 C/T MT-ND6 112 V/M . . SNHL Reported
14430 A/G MT-ND6 82 W/R . . Thyroid Cancer Reported
14439 G/A MT-ND6 79 P/S . . Mitochondrial Respiratory Chain Disorder Reported
14453 G/A MT-ND6 74 A/V rs199476107 Pathogenic MELAS Reported
14459 G/A MT-ND6 72 A/V rs199476105 Pathogenic LDYT/Leigh Disease Cfrm
14482 C/A MT-ND6 64 M/I rs199476108 Pathogenic LHON Cfrm
14482 C/G MT-ND6 64 M/I rs199476108 Pathogenic LHON Cfrm
14484 T/C MT-ND6 64 M/V rs199476104 Pathogenic|Likely pathogenic LHON Cfrm
14487 T/C MT-ND6 63 M/V rs199476109 Pathogenic Dystonia/Leigh Disease/Ataxia/Ptosis/Epilepsy Cfrm
14495 A/G MT-ND6 60 L/S rs199476106 Pathogenic LHON Cfrm
14498 T/C MT-ND6 59 Y/C rs869025186 Pathogenic LHON Reported
14568 C/T MT-ND6 36 G/S rs397515506 Pathogenic LHON Cfrm
14596 A/T MT-ND6 26 I/M rs387906424 Pathogenic LHON Reported
14597 A/G MT-ND6 26 I/T rs797045055 Likely pathogenic . .
14598 T/C MT-ND6 26 I/V rs1057518882 Likely pathogenic . .
14600 G/A MT-ND6 25 P/L . . Leigh Disease/optic atrophy Reported
6277 G/A MT-CO1 125 G/D rs281865417 Pathogenic . .
6328 C/T MT-CO1 142 S/F rs267606883 Pathogenic EXIT (Exercise Intolerance) Reported
6340 C/T MT-CO1 146 T/I . . Prostate Cancer Reported
8668 T/C MT-ATP6 48 W/R . . LHON Reported
6480 G/A MT-CO1 193 V/I rs199476128 Pathogenic Prostate Cancer/enriched in POAG cohort Reported
6489 C/G MT-CO1 196 L/V rs28461189 Pathogenic . .
6489 C/A MT-CO1 196 L/I rs28461189 Pathogenic Therapy-Resistant Epilepsy Reported
6597 C/A MT-CO1 232 Q/K . . MELAS-like syndrome Reported
6721 T/C MT-CO1 273 M/T rs199476127 Pathogenic Acquired Idiopathic Sideroblastic Anemia Reported
6742 T/C MT-CO1 280 I/T rs199476126 Pathogenic Acquired Idiopathic Sideroblastic Anemia Reported
8528 T/C MT-ATP6 1 M/T rs387906422 Pathogenic Infantile cardiomyopathy Confirmed
6955 G/A MT-CO1 351 G/D . . Mild EXIT and MR Reported
7023 G/A MT-CO1 374 V/M . . MELAS-like syndrome Reported
7041 G/A MT-CO1 380 V/I . . Prostate Cancer Reported
7080 T/C MT-CO1 393 F/L . . Prostate Cancer Reported
7083 A/G MT-CO1 394 I/V . . Prostate Cancer Reported
8741 T/G MT-ATP6 72 L/R . . MILS protective factor Reported
7275 T/C MT-CO1 458 S/P rs267606884 Pathogenic . .
7305 A/C MT-CO1 468 M/L . . Prostate Cancer Reported
7587 T/C MT-CO2 1 M/T rs199474825 Pathogenic Mitochondrial Encephalomyopathy Reported
7623 C/T MT-CO2 13 T/I . . LHON Reported
7637 G/A MT-CO2 18 E/K . . PD risk factor Reported
7671 T/A MT-CO2 29 M/K rs199474827 Pathogenic MM Reported
7706 G/A MT-CO2 41 A/T . . Alpers-Huttennlocher-like Reported
8795 A/G MT-ATP6 90 H/R . . MILS protective factor Reported
7877 A/C MT-CO2 98 K/Q . . PEG glaucoma Reported
7989 T/C MT-CO2 135 L/P . . Rhabdomyolysis Reported
8009 G/A MT-CO2 142 V/M rs199474826 Pathogenic . .
8010 T/C MT-CO2 142 V/A . . Developmental delay,ataxia,seizure,hypotonia,lactic acidosis Reported
8021 A/G MT-CO2 146 I/V . . Asthenozoospermia Reported
8108 A/G MT-CO2 175 I/V . . SNHL Reported
8836 A/G MT-ATP6 104 M/V . . LHON Reported
8839 G/C MT-ATP6 105 A/P rs369202065 Pathogenic . .
8839 G/A MT-ATP6 105 A/T rs369202065 Pathogenic . .
9237 G/A MT-CO3 11 V/M rs1057516064 Likely pathogenic . .
9267 G/C MT-CO3 21 A/P . . MIDD Reported
8851 T/C MT-ATP6 109 W/R rs199476136 Pathogenic BSN Reported
9387 G/A MT-CO3 61 V/M . . Asthenozoospermia Reported
9478 T/C MT-CO3 91 V/A rs587776437 Pathogenic Leigh Disease Reported
9544 G/A MT-CO3 113 G/E . . Sporadic bilateral optic neuropathy Reported
8558 C/T MT-ATP6 11 A/V . . Possibly LVNC cardiomyopathy-associated Reported
9660 A/C MT-CO3 152 M/L . . LHON Reported
8890 A/G MT-ATP6 122 K/E . . Juevnile-onset metabolic syndrome Reported
9738 G/T MT-CO3 178 A/S . . LHON Reported
9789 T/C MT-CO3 195 S/P . . Myopathy Reported
8561 C/G MT-ATP6 12 P/R . . Ataxia neuropathy,DM,SNHL,and hypogonadism Reported
9804 G/A MT-CO3 200 A/T rs200613617 Pathogenic LHON Reported
9957 T/C MT-CO3 251 F/L . . PEM/MELAS/NAION Reported
9972 A/C MT-CO3 256 I/L . . EXIT & APS2 - possible link Reported
14753 C/T MT-CYB 3 P/S rs527236162 Likely pathogenic . .
14766 C/A MT-CYB 7 T/N rs193302980 Likely pathogenic . .
14766 C/T MT-CYB 7 T/I rs193302980,rs527236041 Likely pathogenic . .
14766 C/G MT-CYB 7 T/S rs193302980 Likely pathogenic . .
14783 T/G MT-CYB 13 L/V rs193302982 Likely pathogenic . .
14783 T/A MT-CYB 13 L/M rs193302982 Likely pathogenic . .
14784 T/C MT-CYB 13 L/S rs527236163 Likely pathogenic . .
14831 G/A MT-CYB 29 A/T rs199795644 Pathogenic LHON Reported
14841 A/G MT-CYB 32 N/S . . LHON helper mut. Reported
14846 G/A MT-CYB 34 G/S rs207459998 Pathogenic EXIT Reported
14849 T/C MT-CYB 35 S/P rs207460004 Pathogenic EXIT/Septo-Optic Dysplasia Confirmed
14864 T/C MT-CYB 40 C/R . . MELAS Confirmed
14891 C/G MT-CYB 49 L/V rs386419981 Likely pathogenic . .
14905 G/T MT-CYB 53 M/I rs193302983 Likely pathogenic . .
14905 G/C MT-CYB 53 M/I rs193302983 Likely pathogenic . .
14985 G/A MT-CYB 80 R/H rs207459995 Pathogenic . .
15024 G/A MT-CYB 93 C/Y . . Possible DEAF modifier Reported
15060 G/A MT-CYB 105 G/E rs1057516072 Likely pathogenic . .
8950 G/A MT-ATP6 142 V/I . . LDYT Reported
15092 G/A MT-CYB 116 G/S . . MELAS Reported
15098 A/G MT-CYB 118 I/V rs527236172 Likely pathogenic . .
15197 T/C MT-CYB 151 S/P rs207460001 Pathogenic EXIT Reported
15209 T/C MT-CYB 155 Y/H . . Prader-Willi syndrome Reported
15243 G/A MT-CYB 166 G/E . . HCM Reported
15246 G/A MT-CYB 167 G/D rs1057516075 Likely pathogenic . .
8969 G/A MT-ATP6 148 S/N rs794726857 Pathogenic Mitochondrial myopathy,lactic acidosis and sideroblastic anemia(MLASA) Reported
15301 G/T MT-CYB 185 L/F rs193302991 Likely pathogenic . .
15301 G/C MT-CYB 185 L/F rs193302991 Likely pathogenic . .
15314 G/A MT-CYB 190 A/T rs527236176 Likely pathogenic . .
15323 G/A MT-CYB 193 A/T rs527236177 Likely pathogenic . .
15326 A/G MT-CYB 194 T/A rs2853508 Likely pathogenic . .
15349 C/A MT-CYB 201 H/Q rs527236201 Likely pathogenic,Likely pathogenic . .
15363 A/G MT-CYB 206 N/S rs527236182 Likely pathogenic . .
15395 A/G MT-CYB 217 K/E . . Possible LHON factor Reported
15431 G/C MT-CYB 229 A/P rs193302993 Likely pathogenic . .
15431 G/A MT-CYB 229 A/T rs527236208,rs193302993 Likely pathogenic . .
15431 G/T MT-CYB 229 A/S rs193302993 Likely pathogenic . .
15452 C/A MT-CYB 236 L/I rs193302994,rs527236209 Likely pathogenic . .
15452 C/T MT-CYB 236 L/F rs193302994 Likely pathogenic . .
15453 T/C MT-CYB 236 L/P rs527236184 Likely pathogenic Isolated complex III deficiency Reported
15458 T/C MT-CYB 238 S/P rs527236185 Likely pathogenic . .
15459 C/T MT-CYB 238 S/F rs527236186 Likely pathogenic . .
8989 G/C MT-ATP6 155 A/P rs587776444 Pathogenic . .
15498 G/A MT-CYB 251 G/D rs207460003 Pathogenic HiCM/WPW,DEAF Reported
8993 T/G MT-ATP6 156 L/R rs199476133 Pathogenic NARP/Leigh Disease/MILS/other Cfrm
8993 T/C MT-ATP6 156 L/P rs199476133 Pathogenic NARP/Leigh Disease/MILS/other Cfrm

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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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
MToolBox DS 0.48 0.28 0.72 0.06 51.62
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. 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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