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

MitImpact 4 provides functional and pathogenicity annotations for all 49,704 possible mitochondrial single-nucleotide variants, including tRNA and rRNA, with ACMG/AMP-ready posterior probabilities.

• Why it matters: Mitochondrial variant interpretation has largely ignored tRNA and rRNA because their effects depend on RNA structure and dedicated predictors are limited.
• What they did: The team built a genome-wide database that annotates each variant with functional consequence, phylogenetic conservation, local mutational constraint, and population frequency from gnomAD, HelixMTdb, and ToMMo. Missense variants use APOGEE 2 plus AlphaMissense, ESM1b, VARITY, and LIST-S2, while tRNA/rRNA variants use nAPOGEE plus MitoTIP and PON-mt-tRNA, with posterior probabilities and ClinVar/MITOMAP integration.
• The result: ClinVar and MITOMAP clinical evidence, including ClinGen expert-panel classifications, is integrated with VCF upload in a redesigned interface, enabling ACMG/AMP framework use for mitochondrial DNA variant interpretation.