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Peer-reviewedCC BY-NC 4.0Nucleic Acids Research

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

  • Agnese Giovannetti1
  • Alessandro Napoli1
  • Niccolò Liorni1
  • Francesco Petrizzelli1
  • Tommaso Biagini1
  • Antonio Gasbarrini2,3
  • Viviana Caputo4
  • Tommaso Mazza1
4 affiliations
  1. 1Computational Biology and Bioinformatics Laboratory, Fondazione Policlinico Universitario A. Gemelli IRCCS , Rome, 00168 ,
  2. 2CeMAD Translational Research Laboratories, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS , Rome, 00168 ,
  3. 3Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore , Rome, 00168 ,
  4. 4Department of Experimental Medicine, Sapienza University of Rome , Rome, 00161 ,
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{giovannetti2026mitimpact,
  title = {{MitImpact 4: a genome-wide resource for the interpretation of coding and non-coding mitochondrial DNA variants}},
  author = {Agnese Giovannetti and Alessandro Napoli and Niccolò Liorni and Francesco Petrizzelli and Tommaso Biagini and Antonio Gasbarrini and Viviana Caputo and Tommaso Mazza},
  journal = {Nucleic Acids Research},
  year = {2026},
  month = oct,
  doi = {10.1093/nar/gkag1070},
  url = {https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkag1070/9004249},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - MitImpact 4: a genome-wide resource for the interpretation of coding and non-coding mitochondrial DNA variants
AU  - Agnese Giovannetti
AU  - Alessandro Napoli
AU  - Niccolò Liorni
AU  - Francesco Petrizzelli
AU  - Tommaso Biagini
AU  - Antonio Gasbarrini
AU  - Viviana Caputo
AU  - Tommaso Mazza
PY  - 2026
DA  - 2026/10/29
JO  - Nucleic Acids Research
DO  - 10.1093/nar/gkag1070
UR  - https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkag1070/9004249
AB  - 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.
SN  - 0305-1048
SN  - 1362-4962
ER  -