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Legend of the output


    General info

  1. Chr: the reference sequence for the human mtDNA is the Revised Cambridge Reference Sequence; NCBI accession number: NC_012920.1
  2. Start: genomic start position for the variant
  3. End: genomic end position for the variant
  4. Ref: reference nucleotide
  5. Alt: alternative nucleotide
  6. MitImpact id: variant identifier in MitImpact
  7. Gene symbol: official gene symbol
  8. Respiratory Chain complex: Respiratory Chain Complex which the mitochondrial protein belongs to
  9. Ensembl gene id: identifier from Ensembl Gene (ref)
  10. Ensembl protein id: identifier from Ensembl Protein
  11. Ensembl transcript id: identifier from Ensembl transcript
  12. Uniprot name: gene symbol in Uniprot (ref)
  13. Uniprot id: protein accession number in Uniprot
  14. NCBI gene id: gene identifier in NCBI Gene (ref)
  15. NCBI protein id: protein identifier in NCBI RefSeq Protein (ref)
  16. Gene position: variant position relative to the coordinates of the gene
  17. AA pos: amino acid position
  18. AA ref: reference amino acid
  19. AA alt: alternative amino acid
  20. Codon substitution: Codon substitution relative to the genomic variant

    21. Conservation

  21. PhyloP 100V: PhyloP conservation index from UCSC Table Browser 2015 (ref). [min -20, max 10] Predicted accelerated evolution: score <= 0; Conserved: score > 0
  22. PhastCons 100V: PhastCons conservation index from UCSC Table Browser 2015 (ref). [min 0, max 1] Non-conserved: score <= 0.7; Conserved: score > 0.7 (soft threshold)

    23. Pathogenicity predictors

  23. PolyPhen2: categorical prediction for PolyPhen ver. 2.2.2, HumDiv dataset (ref)
  24. PolyPhen2 score: [0.0-1.0]. Neutral: score <= 0.15; Possibly damaging: 0.15 < score <= 0.85; Probably damaging: score > 0.85
  25. SIFT: categorical prediction for SIFT ver. 5.0.3 (ref)
  26. SIFT score: [0.0-1.0]. Neutral: score > 0.05; Deleterious: score <= 0.05
  27. SIFT4G: categorical prediction for SIFT4G (ref)
  28. SIFT4G score: [0.0-1.0]. Neutral: score > 0.05; Deleterious: score <= 0.05
  29. FatHmm: categorical prediction for FatHmm ver. 2.2 (unweighted version) (ref)
  30. FatHmm score: [min -15, max 10]. Neutral: score > -3; Deleterious: score <= -3
  31. FatHmmW: categorical prediction for FatHmm ver. 2.3 (weighted version)
  32. FatHmmW score: [min -3, max 6]. Neutral: score > -1.5; Deleterious: score <= -1.5
  33. PROVEAN: categorical prediction for PROVEAN ver. 1.3 (ref)
  34. PROVEAN score: [min -14, max 14]. Neutral: score > -2.5; Deleterious: score <= -2.5 (soft threshold)
  35. MutationAssessor: categorical prediction for MutationAssessor ver. 2.0 (ref)
  36. MutationAssessor score: [min -6, max 6]. Neutral: score <= 0.8; Low impact: 0.8 < score <= 1.9 Medium impact: 1.9 < score <= 3.5 High impact: score > 3.5
  37. EFIN SP: score for EFIN, trained with the SwissProt dataset (ref)
  38. EFIN SP score: [min 0, max 1]. Neutral: score > 0.6; Damaging: score <= 0.6
  39. EFIN HD: score for EFIN, trained with the HumDiv dataset (ref)
  40. EFIN HD score: [min 0, max 1]. Neutral: score > 0.28; Damaging: score <= 0.28
  41. VEST: categorical prediction for VEST ver. 1.3 (ref)
  42. VEST score: [min 0, max 1]. Neutral: p-value > 0.05; Pathogenic: p-value <= 0.05. The score was computed using CRAVAT 3.2 (ref)
  43. PANTHER: categorical prediction for PANTHER (ref)
  44. PANTHER score: [min 0, max 1]. Neutral: score < 0.5; Disease: score >= 0.5. The score was computed using Meta-SNP (ref)
  45. PhD-SNP: categorical prediction for PhD-SNP
  46. PhD-SNP score: [min 0, max 1]. Neutral: score < 0.5; Disease: score >= 0.5. The score was computed using Meta-SNP (ref)
  47. MutationTaster: Mutation Taster categorical prediction (ref)
  48. MutationTaster score: [min 0, max 1]. Polymorphism: score < 0.5; Disease causing: score >= 0.5
  49. CADD: categorical prediction for CADD ver. 1.3 (ref)
  50. CADD phred score: [min 0, max 35]. Neutral: score < 20 (soft threshold); Deleterious: score >= 20
  51. SNAP: categorical prediction for SNAP
  52. SNAP score: [min 0, max 1]. Neutral: score < 0.5; Disease: score >= 0.5. The score was computed using Meta-SNP (ref)
  53. Mitoclass.1: categorical prediction only for MitoClass.1 (ref)
  54. SNPDryad: categorical prediction for SNPDryad (ref)
  55. SNPDryad score: [min 0, max 1]. No hard-thresholds were indicated by authors. Indicatively: Neutral: score < 0.9; Pathogenic: score >= 0.9

    56. Pathogenicity meta-predictors

  56. APOGEE1: categorical prediction for APOGEE1 [Neutral, Pathogenic] - (December 2022)
  57. APOGEE1 score: Neutral: score ≤ 0.5; Pathogenic: score > 0.5 - [min 0, max 1]
  58. APOGEE2: categorical prediction for APOGEE2 [Benign, Likely-benign, VUS, Likely-pathogenic, Pathogenic] - (December 2022)
  59. APOGEE2 score: Benign: score ≤ 0.06157; Likely-benign: 0.06157 < score ≤ 0.26529; VUS: 0.26529 < score < 0.71613; Likely-pathogenic: 0.71613 ≤ score < 0.90719; Pathogenic: score ≥ 0.90719 - [min 0, max 1]
  60. APOGEE2 probability: Benign: probability ≤ 0.001; Likely-benign: 0.001 < probability ≤ 0.1; VUS: 0.1 < probability < 0.9; Likely-pathogenic: 0.9 ≤ probability < 0.99; Pathogenic: probability ≥ 0.99 - [min 0, max 1]
  61. CAROL: categorical prediction for CAROL (ref)
  62. CAROL score: [min 0, max 1]. Neutral: score < 0.98; Deleterious: score >= 0.98
  63. Condel: categorical prediction for Condel (ref)
  64. Condel score: [min 0, max 1]. Neutral: score < 0.5; Deleterious: score >= 0.5
  65. COVEC WMV: categorical prediction for the COVEC ver. 0.4 Weighted Majority Rule consensus method (ref)
  66. COVEC WMV score: [min -6, max 6]. Neutral: score < 0; Deleterious: score > 0; Inaccurate prediction: score = 0
  67. Meta-SNP: categorical prediction for Meta-SNP (ref)
  68. Meta-SNP score: [min 0, max 1]. Neutral: score < 0.5; Disease: score >= 0.5
  69. MtoolBox: categorical prediction for MtoolBox (ref)
  70. MtoolBox DS: [min 0, max 1]. Neutral: score < 0.43; Deleterious: score >= 0.43
  71. DEOGEN2: DEOGEN2 categorical prediction (ref)
  72. DEOGEN2 score: [min 0, max 1]. Neutral: score < 0.5; Deleterious: score >= 0.5

    73. Cancer-specific predictors

  73. PolyPhen2 transf: transformed PolyPhen2 categorical prediction by TransFIC ver. 1.0 (ref)
  74. PolyPhen2 transf score: [min -5, max 5]. Low impact: score <= -1; Medium impact: -1 < score < 1.5 (soft threshold); High impact: score >= 1.5 (soft threshold)
  75. SIFT transf: transformed SIFT categorical prediction
  76. SIFT transf score: [min -5, max 5]. Low impact: score < -1; Medium impact: -1 < score < 2 (soft threshold); High impact: score >= 2 (soft threshold)
  77. MutationAssessor transf: Transformed MutationAssessor categorical prediction
  78. MutationAssessor transf score: [min -5, max 5]. Low impact: score < 2; Medium impact: -1 < score < 2 (soft threshold); High impact: score >= 2 (soft threshold)
  79. CHASM: CHASM categorical rpediction, as computed by CRAVAT 3.2 (ref)
  80. CHASM FDR: [min 0, max 1]. Neutral: FDR > 0.2; Driver: FDR <= 0.2

    81. Databases Phenotypes

  81. ClinVar July2022 Variation id: variation accession number
  82. ClinVar July2022 CLNSIG: variant clinical significance (dbSNP-ClinVar, updated in July 2022)
  83. ClinVar July2022 CLNDN: disease name associated with a variant
  84. ClinVar July2022 CLNDISDB: disease database name for a variant
  85. MITOMAP Allele: allele description for a variant, as reported in the MITOMAP database (July 2022)
  86. MITOMAP Disease Het/Hom: + if a variant was found in heteroplasmy (left) and/or homoplasmy (right)
  87. MITOMAP Disease Clinical info: phenotypes associated with a variant
  88. MITOMAP Disease Status: validation status for a variant (refer to this for details)
  89. MITOMAP Disease GenBank Freq: GenBank frequency information of a variant of the MITOMAP Disease set
  90. MITOMAP Disease GenBank Seqs: GenBank sequences where a variant of the MITOMAP Disease set was found
  91. MITOMAP Disease GenBank Curated refs: GenBank curated sequences where a variant of the MITOMAP Disease set was found
  92. MITOMAP General GenBank Freq: GenBank frequency information of a variant of the MITOMAP General set
  93. MITOMAP General GenBank Seqs: GenBank sequences where a variant of the MITOMAP General set was found
  94. MITOMAP General GenBank Curated refs: GenBank curated sequences where a variant of the MITOMAP General set was found
  95. gnomAD 3.1 filter: Reliability flag
  96. gnomAD 3.1 AC hom: Allele count of homoplasmic variants
  97. gnomAD 3.1 AC het: Allele count of heteroplasmic variants
  98. gnomAD 3.1 AF hom: Allelic frequency of homoplasmic variants
  99. gnomAD 3.1 AF het: Allelic frequency of heteroplasmic variants
  100. gnomAD 3.1 AN: Total alleles number (Info)
  101. HelixMTdb AC hom: Allele count of homoplasmic variants
  102. HelixMTdb AF hom: Allelic frequency of homoplasmic variants
  103. HelixMTdb AC het: Allele count of heteroplasmic variants
  104. HelixMTdb AF het: Allelic frequency of heteroplasmic variants/li>
  105. HelixMTdb mean ARF: Mean Alternate Read Fraction (for heteroplasmic variants)
  106. HelixMTdb max ARF: Max Alternate Read Fraction (for heteroplasmic variants)
  107. COSMIC 90 id: accession number for a cancer-associated variant in COSMIC ver. 90
  108. dbSNP 155 id: accession number for a variant in dbSNP ver. 155

    109. Residue interaction

  109. EVmutation: EVmutation score of pairs of amino acid variants. Scores are reported as gene: pos1aa1-pos2 aa2 → score (ref)§
  110. Site A-B InterP: predicted co-varying amino acid sites of two interacting proteins by I-COMS, using the corrected Mutual Information and Direct Coupling Analysis methods. Any pair is described as protein1:pos1-protein2:pos2 §
  111. Site A-B IntraP: predicted co-varying amino acid sites located in the same protein by I-COMS. Any pair is described as protein1:pos1-protein1: pos2§
  112. ΔΔG intraP: Free energy change of folding (ΔΔG, Kcal/mol) of pairs of co-varying amino acid variants (protein1:var1:var2). Upon selection, the righmost canvas will draw the 3D model of protein1, which will highlight both variants and will report: the ΔΔG value of both variants if considered together; the ΔΔG value for var1; the ΔΔG value for var2 (ref)#
  113. ΔΔG intraP interface: ΔΔGbind of interaction energy. Both variants of the pair belong to one of the proteins and are located in their interaction interface (protein1:protein2:PDB ID: PDB chain protein1: PDB chain protein2: var1: var2). As from above, the rightmost canvas will display: the ΔΔGbind value of both variants if considered together; the ΔΔGbind value for var1 in protein1; the ΔΔGbind value for var2 in protein1 #.
  114. ΔΔG interP: ΔΔGbind of interaction energy calculated as the energetic difference between wild-type and mutant proteins. Variants are located in different proteins (protein1:protein2:PDB ID: PDB chain protein1: PDB chain protein2: var1: var2). As from above, the rightmost canvas will display: the ΔΔGbind value of both variants if considered together; the ΔΔGbind value for var1 in protein1; the ΔΔGbind value for var2 in protein2 #.
    § Co-variation scores (i.e., EV score, mfDCA, and corrected MI) are not meant to prioritize one pair over another, since all reported pairs of co-varying variants were selected from the top scoring pairs obtained as explained in the Description page.
    # ΔΔG values >±0.61 Kcal/mol are indicative of disrupting variants. ΔΔG values close to zero (<±0.1 Kcal/mol) are indicative of possibly compensating double mutants, as explained in the Description page.

    Compensated Pathogenic Deviations (ref, ref)

  115. Frequency: frequency of a CPD variant; it is the proportion of aligned orthologous sequences that carry a specific human pathogenic variant as wild-type amino acid on the total number of aligned sequences. In our analysis, the total number of aligned orthologous sequences is 673 (for CYB, ND6) or 674 (ND1, ND2, CO1, CO3) or 675 (all remaining genes)
  116. AA ref: reference amino acid for the CPD, considering the human protein reference sequence, as indicated in the General Info section
  117. AA alt: alternate amino acid found in the position specified by the aln pos field, within non-human mammalian species (see species name, RefSeq Protein ID, and NCBI Taxon ID)
  118. Aln pos: position of the CPD within the ortholog proteins alignment; the reference is the human sequence
  119. RefSeq protein id: protein sequence identifier within the NCBI RefSeq Protein Database
  120. Species name: scientific species name carrying the CPD variant as wild-type amino acid
  121. NCBI taxon id: species identifier from the NCBI Taxonomy database