rs121909724
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_002437.5(MPV17):c.359G>A(p.Trp120Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000124 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
MPV17
NM_002437.5 stop_gained
NM_002437.5 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 3.99
Genes affected
MPV17 (HGNC:7224): (mitochondrial inner membrane protein MPV17) This gene encodes a mitochondrial inner membrane protein that is implicated in the metabolism of reactive oxygen species. Mutations in this gene have been associated with the hepatocerebral form of mitochondrial DNA depletion syndrome (MDDS). [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-27312510-C-T is Pathogenic according to our data. Variant chr2-27312510-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MPV17 | NM_002437.5 | c.359G>A | p.Trp120Ter | stop_gained | 5/8 | ENST00000380044.6 | |
MPV17 | XM_005264326.5 | c.359G>A | p.Trp120Ter | stop_gained | 5/8 | ||
MPV17 | XM_017004151.2 | c.311G>A | p.Trp104Ter | stop_gained | 5/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MPV17 | ENST00000380044.6 | c.359G>A | p.Trp120Ter | stop_gained | 5/8 | 1 | NM_002437.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152224Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251298Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135800
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461800Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727184
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mitochondrial DNA depletion syndrome 6 (hepatocerebral type) Pathogenic:2
Likely pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Aug 13, 2019 | This variant is interpreted as a Likely pathogenic for Mitochondrial DNA depletion syndrome 6, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PVS1-strong, PP1, PM3-supporting. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2008 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 21, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 18695062). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16164). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp120*) in the MPV17 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MPV17 are known to be pathogenic (PMID: 23714749). - |
Charcot-Marie-Tooth disease, axonal, type 2EE Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 05, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A;A;A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at