MitImpact 4: a genome-wide resource for the interpretation of coding and non-coding mitochondrial DNA variants

Annotation database of all 49,704 possible mitochondrial DNA SNVs: missense predictors, tRNA- and rRNA-specific predictors, posterior probabilities of pathogenicity

MitImpact 4 now covers all 49,704 single-nucleotide variants that can occur in the mitochondrial genome, no longer only those of the 13 protein-coding genes. Each variant is annotated for functional consequence, phylogenetic conservation, local mutational constraint and population frequency in gnomAD, HelixMTdb and ToMMo. Missense variants are scored with APOGEE 2 and newly added predictors (AlphaMissense, ESM1b, VARITY, LIST-S2), while tRNA and rRNA variants receive nAPOGEE, the authors' RNA-specific model, alongside MitoTIP and PON-mt-tRNA. For both classes, scores come with posterior probabilities of pathogenicity that can be used within the ACMG/AMP framework for mitochondrial DNA. Clinical annotation from ClinVar and MITOMAP, including ClinGen expert-panel classifications, is integrated in an interface that also annotates user-submitted VCF files.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

tRNA and rRNA genes carry a disproportionate share of known pathogenic alleles and remained a blind spot of interpretation: posterior probabilities directly usable for mitochondrial ACMG/AMP criteria are a concrete gain for mitochondrial variants detected on genome data. The abstract, however, reports no performance metric for nAPOGEE and no calibration of these probabilities, which should be checked before using them as a classification argument.

Analysis by Dr Thibaut Benquey