2-27322443-C-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_002437.5(MPV17):c.70+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000124 in 1,613,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_002437.5 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MPV17 | NM_002437.5 | c.70+5G>A | splice_region_variant, intron_variant | Intron 2 of 7 | ENST00000380044.6 | NP_002428.1 | ||
MPV17 | XM_005264326.5 | c.70+5G>A | splice_region_variant, intron_variant | Intron 2 of 7 | XP_005264383.1 | |||
MPV17 | XM_017004151.2 | c.-75+5G>A | splice_region_variant, intron_variant | Intron 1 of 7 | XP_016859640.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152266Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461430Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727022
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152266Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74382
ClinVar
Submissions by phenotype
not provided Pathogenic:2
This sequence change falls in intron 2 of the MPV17 gene. It does not directly change the encoded amino acid sequence of the MPV17 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs267607268, gnomAD 0.007%). This variant has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 18329934). ClinVar contains an entry for this variant (Variation ID: 2581455). Studies have shown that this variant alters MPV17 gene expression (PMID: 18329934). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 2, but is expected to preserve the integrity of the reading-frame (PMID: 18329934, 20614188). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
RNA studies demonstrate a damaging effect: [alternative splicing resulting in skipping of exon 2] (PMID: 18329934, 20614188); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25525159, 20614188, 18329934) -
Mitochondrial DNA depletion syndrome Pathogenic:1
Variant summary: MPV17 c.70+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the 5' canonical splicing donor site. One predicts the variant abolishes the 5 canonical splicing donor site. At least two publications report in vivo and in vitro experimental evidence that this variant affects normal mRNA splicing by skipping exon 2 and normal mRNA product of MPV17 is abolished (Navarro-Sastre_2008 and 2010). The variant allele was found at a frequency of 3.2e-05 in 31410 control chromosomes. c.70+5G>A has been reported in the literature at a homozygous state in two individuals affected with severe hepatopathy, polyneuropathy, neurological regression with Leukodystrophy, and other characteristic symptoms of mitochondrial diseases (example, Navarro-Sastre_2008 and 2010). These data indicate that the variant is very likely to be associated with MPV17 Related Mitochondrial DNA Depletion Syndrome. The following publications have been ascertained in the context of this evaluation (PMID: 20614188, 18329934). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at