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Mitochondrial DNA variants are a frequent cause of inherited disease, yet their computational interpretation has focused almost exclusively on the 13 protein-coding genes. Variants in tRNA and rRNA genes, which carry a disproportionate share of the known pathogenic alleles, have remained a diagnostic blind spot, because their effect depends on RNA structure rather than on protein sequence and few dedicated predictors exist. MitImpact 4 removes this asymmetry. The database now covers all 49 704 single-nucleotide variants that can occur in the mitochondrial genome and reports their functional consequence, phylogenetic conservation, local mutational constraint, and population frequency in gnomAD, HelixMTdb, and ToMMo. Missense variants are annotated with APOGEE 2 and with newly added predictors, including AlphaMissense, ESM1b, VARITY, and LIST-S2, while tRNA and rRNA variants receive predictions from nAPOGEE, our RNA-specific model, alongside MitoTIP and PON-mt-tRNA. For both classes, scores are accompanied by 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 a redesigned interface that also annotates user-submitted VCF files. MitImpact 4 is freely available at https://mitimpact.mcb2lab.org.

Numerous lines of evidence have shown that the interaction between the nuclear and mitochondrial genomes ensures the efficient functioning of the OXPHOS complexes, with substantial implications in bioenergetics, adaptation, and disease. Their interaction is a fascinating and complex trait of the eukaryotic cell that MitImpact explores with its third major release. MitImpact expands its collection of genomic, clinical, and functional annotations of all non-synonymous substitutions of the human mitochondrial genome with new information on putative Compensated Pathogenic Deviations and co-varying amino acid sites of the Respiratory Chain subunits. It further provides evidence of energetic and structural residue compensation by techniques of molecular dynamics simulation. MitImpact is freely accessible at http://mitimpact.css-mendel.it.

Mitochondrial DNA carries a tiny, but fundamental portion of the eukaryotic genetic code. As its nuclear counterpart, it is susceptible to point mutations. Their level of pathogenicity has been assessed for the newly discovered mutations only, leaving some degree of uncertainty on the potential impact of the unknown mutations. Here we present Mitochondrial mutation Impact (MitImpact), a queryable lightweight web interface to a reasoned collection of structurally and evolutionary annotated pathogenicity predictions, obtained by assembling pre-computed with on-the-fly-computed sets of pathogenicity estimations, for all the possible mitochondrial missense variants. It presents itself as a resource for fast and reliable evaluation of gene-specific susceptibility of unknown and verified amino acid changes. MitImpact is freely available at http://bioinformatics.css-mendel.it/ (tools section). ©2014 Wiley Periodicals, Inc.