Extended Data Fig. 2: Mutability, disease-associated variation, and constraint across classes of human mtDNA variation.
From: Quantifying constraint in the human mitochondrial genome
(a) Trinucleotide mutational signature of mtDNA mutations within the OriB-OriH region (m.16197-191) predicted by the composite likelihood model. Mutation likelihoods for the six pyrimidine base substitution types across 96 trinucleotides are shown, colored by whether the reference nucleotide is in the reference ‘light’ or reverse complement ‘heavy’ strand. (b) Proportion of total disease-associated variants in ClinVar (n = 2607) and MITOMAP (n = 882) by consequence. (c) The observed:expected ratio of ClinVar Uncertain Significance and MITOMAP Reported mtDNA variants in gnomAD, and subset by whether they met pathogenic or benign criteria for computational algorithms and MITOMAP population frequency in ACMG/AMP guidelines for mtDNA variant interpretation. 1000 ClinVar variants (with pathogenic evidence, n = 147; note none satisfied both benign criteria) and 791 MITOMAP variants (with pathogenic evidence, n = 175; with benign evidence, n = 28) are included. (d) The observed:expected ratio of in silico predictions in gnomAD for missense variants by APOGEE (pathogenic, n = 7276 and neutral, n = 16,800), and for tRNA variants by MitoTIP (likely pathogenic, n = 981; possibly pathogenic, n = 1171, possibly benign, n = 1162 and likely benign, n = 1198) and HmtVar (pathogenic, n = 202; likely pathogenic, n = 6, likely polymorphic, n = 4139 and polymorphic, n = 24); all of which are recommended per ACMG/AMP mtDNA guidelines for variant interpretation. Note the outlier HmtVar ‘likely pathogenic’ group only includes six variants. (e) Assessment of functional classes of mtDNA variation in a replication dataset, HelixMTdb. The n per class is per Fig. 1d. The diamonds in (c-e) represent the observed:expected ratio, and the error bars in (c-e) represent 90% confidence intervals.
