2-27312684-T-G
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_002437.5(MPV17):c.275A>C(p.Asp92Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D92G) has been classified as Pathogenic.
Frequency
Consequence
NM_002437.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MPV17 | NM_002437.5 | c.275A>C | p.Asp92Ala | missense_variant | Exon 4 of 8 | ENST00000380044.6 | NP_002428.1 | |
MPV17 | XM_005264326.5 | c.275A>C | p.Asp92Ala | missense_variant | Exon 4 of 8 | XP_005264383.1 | ||
MPV17 | XM_017004151.2 | c.227A>C | p.Asp76Ala | missense_variant | Exon 4 of 8 | XP_016859640.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
The D92A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D92A variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D92A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret D92A to be likely pathogenic; however, the possibility that it is benign cannot be excluded. -
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not specified Uncertain:1
Variant summary: MPV17 c.275A>C (p.Asp92Ala) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251476 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.275A>C has been reported in the literature in the compound heterozygous state in an individual affected with mitochondrial hepatopathy (Van Hove_2024). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 38180987). ClinVar contains an entry for this variant (Variation ID: 392127). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at