Legend of the output
Meaning, thresholds and sources for every annotation column.
General info
Mithril id / MitImpact id
internal variant identifiers. Every variant has a Mithril id; MitImpact id is additionally assigned to protein-coding (missense) variants.
Chromosome
reference sequence is the Revised Cambridge Reference Sequence; NCBI accession NC_012920.1.
Start
genomic position of the variant.
Alleles (Ref/Alt)
reference and alternate nucleotide.
Molecule type (column: class)
molecular class of the affected feature:
protein-coding, tRNA, rRNA, control region (D-loop) or intergenic.Gene symbol
official gene symbol.
Gene position / start / end / strand
variant position relative to, and coordinates/strand of, the gene or genomic region (D-loop or intergenic) involved.
Codon substitution
codon change for the genomic variant (protein-coding only). Where a termination codon is completed by 3′ A additions to the mRNA, indicated with ".".
AA pos / AA ref / AA alt
amino-acid position and reference/alternate amino acid (protein-coding only). Termination codons shown as "*".
General functional effect
effect on the genomic sequence assessed with SnpEff (e.g. missense, stop lost/gained, start lost, synonymous, non-coding, intergenic).
Detailed functional effect
detailed SnpEff effect. A WARNING tag flags variants modifying the first AUU/GUG/AUC codon, considered functional start codons in MITOMAP.
OMIM id
gene identifier in OMIM.
HGVS
variant nomenclature per HGVS.
HGNC
gene identifier in HGNC.
Respiratory Chain complex
complex of the related mitochondrial protein.
Conservation
PhyloP 100V
100-vertebrate basewise conservation (UCSC hg38, 2015) [−20, 30]. Accelerated evolution: score ≤ 0; Conserved: score > 0.
PhyloP 470Way
470-mammal basewise conservation (UCSC hg38, 2022) [−20, 30]. Same thresholds as above.
PhastCons 100V
100-vertebrate conservation (UCSC hg38, 2015) [0, 1]. Non-conserved: ≤ 0.7; Conserved: > 0.7 (soft threshold).
PhastCons 470Way
470-mammal conservation (UCSC hg38, 2022) [0, 1]. Same thresholds as above.
General-purpose impact scores
Computed for every variant regardless of molecule type -- missense, tRNA, rRNA, control region and intergenic all carry these.
CADD
categorical prediction (v1.3). phred [0, ∞): Neutral < 20 (soft); Deleterious ≥ 20.
MLC
mitochondrial local constraint. score [0, 1] (soft): Deleterious ≥ 0.5; Neutral < 0.5.
Missense (protein-coding) predictors
PolyPhen2
score [0, 1]: Neutral ≤ 0.15; Possibly damaging 0.15–0.85; Probably damaging > 0.85.
SIFT / SIFT4G
score [0, 1]: Neutral > 0.05; Deleterious ≤ 0.05.
PROVEAN
score [−14, 14]: Neutral > −2.5; Deleterious ≤ −2.5 (soft threshold).
MutationAssessor
score [−5.2, 8.08]: Neutral < 2.65; Low 2.65–5.15; Medium 5.15–6.8; High impact ≥ 6.8.
MutationTaster
categorical prediction (dbNSFP, release 2021): disease-causing (automatic), disease-causing, or polymorphism. score [0, 1]: disease causing: > 0.5; polymorphism: < 0.5.
EFIN SP / EFIN HD
score [0, 1] plus a call: Neutral or Deleterious. SP (SwissProt) threshold ≤ 0.6; HD (HumDiv) threshold ≤ 0.28.
LIST-S2
score [0, 1]: Neutral < 0.85; Deleterious ≥ 0.85.
ESM1b
score [−24.538, 6.937]: Neutral ≥ −7.5; Deleterious < −7.5.
VARITY-R / VARITY-ER
score [0, 1]: Neutral < 0.5; Deleterious ≥ 0.5 (soft threshold).
PANTHER / PhD-SNP
score [0, 1]: Neutral < 0.5; Disease ≥ 0.5.
SNPDryad
score [0, 1]. Indicatively Neutral < 0.9; Pathogenic ≥ 0.9.
Mitoclass.1
categorical prediction without score.
AlphaMissense
categorical prediction. score [0, 1]: Likely pathogenic > 0.56; Ambiguous 0.34–0.56; Likely benign < 0.34.
VEST
p-value: Neutral p > 0.05; Pathogenic p ≤ 0.05 (CRAVAT 3.2). FDR: variant-specific false discovery rate.
Pathogenicity meta-predictors
APOGEE1
categorical [Neutral, Pathogenic]. score [0, 1]: Neutral ≤ 0.5; Deleterious > 0.5.
APOGEE2
seven classes. score [0, 1]: Benign < 0.062; Likely-benign 0.062–0.265; VUS− 0.265–0.396; VUS 0.396–0.544; VUS+ 0.544–0.716; Likely-pathogenic 0.716–0.907; Pathogenic ≥ 0.907.
CAROL
score [0, 1]: Neutral < 0.98; Deleterious ≥ 0.98.
Condel
score [0, 1]: Neutral < 0.5; Deleterious ≥ 0.5.
COVEC WMV
score [−6, 6]: Neutral < 0; Deleterious > 0; Inaccurate = 0.
MToolBox DS
[0, 1]: Neutral < 0.43; Deleterious ≥ 0.43.
DEOGEN2
score [0, 1]: Neutral < 0.5; Deleterious ≥ 0.5.
Meta-SNP
score [0, 1]: Neutral < 0.5; Deleterious ≥ 0.5.
Cancer-specific predictors
PolyPhen2 transf
TransFIC-transformed prediction [−5, 5]. Low impact: ≤ −1; Medium: −1–1.5; High impact: ≥ 1.5.
SIFT transf / MutationAssessor transf
TransFIC-transformed predictions [−5, 5]. Low impact: < −1; Medium: −1–2; High impact: ≥ 2.
CHASM
categorical prediction (CRAVAT 3.2). p-value and FDR [0, 1]: Neutral FDR > 0.2; Driver FDR ≤ 0.2.
tRNA / rRNA pathogenicity
Real predictions for these molecule types were introduced with the MitImpact4 release.
nAPOGEE
categorical class for noncoding (tRNA, rRNA) variants, with score and probability [0, 1]. Scoring currently covers tRNA and rRNA only, with separate ranges:
tRNA: benign ≤ 0.0914; likely benign ≤ 0.4283; VUS− ≤ 0.5232; VUS ≤ 0.5988; VUS+ ≤ 0.6714; likely pathogenic ≤ 0.7607; pathogenic > 0.7607.
rRNA: benign ≤ 0.4304; likely benign ≤ 0.5769; VUS− ≤ 0.6324; VUS ≤ 0.6878; VUS+ ≤ 0.7546; likely pathogenic ≤ 0.8653; pathogenic > 0.8653.
tRNA: benign ≤ 0.0914; likely benign ≤ 0.4283; VUS− ≤ 0.5232; VUS ≤ 0.5988; VUS+ ≤ 0.6714; likely pathogenic ≤ 0.7607; pathogenic > 0.7607.
rRNA: benign ≤ 0.4304; likely benign ≤ 0.5769; VUS− ≤ 0.6324; VUS ≤ 0.6878; VUS+ ≤ 0.7546; likely pathogenic ≤ 0.8653; pathogenic > 0.8653.
MitoTip
tRNA-specific pathogenicity: score [−5.9, 21.8], quartile, count, percentage and MITOMAP status, from MITOMAP. Likely benign: < 8.44; Possibly benign: 8.44–12.66; Possibly pathogenic: 12.66–16.25; Likely pathogenic: > 16.25.
PON-mt-tRNA
tRNA-specific classification, ML probability of pathogenicity and Kondrashov-method prediction. Score [0, 1]: Neutral ≤ 0.5 (soft threshold); Deleterious > 0.5.
Databases & phenotypes
ClinVar
id, ALLELEID, CLNVI, CLNDISDB, CLNDN, CLNSIG and CLNSIGCONF: identifiers, disease database cross-references, disease name, clinical significance and conflicting-interpretation summary.
MITOMAP disease
Hom/Het shows "+" if a variant was found in homoplasmy (left) and/or heteroplasmy (right). GenBank frequency and supporting sequences. Clinical info and Status as reported by MITOMAP.
MITOMAP general
GenBank frequency, supporting sequences and whether the variant is a known MITOMAP variant.
gnomAD
AN, AC/AF hom, AC/AF het and a reliability filter flag (gnomAD 3.1 mtDNA).
HelixMTdb
AC/AF hom & het, plus mean/max alternate read fraction.
ToMMo 61KJPN
allele count, frequency and number in the ToMMo 61KJPN database.
dbSNP
accession in dbSNP v157.
Residue interaction
EVmutation
shown as a network diagram: the queried variant at the center, linked to its top co-varying residues, with edge thickness/opacity proportional to the covariation score.§
Intra-/inter-protein co-variation
shown as a network diagram, same style as EVmutation: the queried residue at the center, linked to co-varying partners in the same protein (IntraP) or a different one (InterP), predicted by I-COMS (corrected Mutual Information and Direct Coupling Analysis). Only the strongest partners by score are drawn (up to 18); weaker ones are counted, not hidden silently.§
ΔΔG intraP
folding free-energy change (ΔΔG, Kcal/mol) of co-varying variant pairs within a protein.#
ΔΔG intraP interface
binding free-energy change (ΔΔGbind) for variant pairs located in a protein–protein interaction interface.#
ΔΔG interP
binding free-energy change between wild-type and mutant proteins, for variants located in different proteins.#
§ Co-variation scores (EV, mfDCA, corrected MI) are not meant to rank pairs; all reported pairs are top-scoring, as explained in the Description.
# ΔΔG values > ±0.61 Kcal/mol indicate disrupting variants; values near zero (< ±0.1 Kcal/mol) indicate possibly compensating double mutants.
Compensated Pathogenic Deviations (CPD)
References: Jordan et al., 2015, Azevedo et al., 2016
Frequency
proportion of aligned orthologous sequences carrying a human pathogenic variant as wild-type amino acid (over 673–675 aligned sequences depending on the gene).
AA ref / AA alt
reference (human) amino acid and the alternate amino acid found in non-human mammalian species at the aligned position.
Aln pos
position of the CPD within the ortholog protein alignment (human sequence as reference).
RefSeq protein id / Species name / NCBI taxon id
identifiers of the species and protein sequence carrying the CPD.