rs147952488
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Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1PM2PP3PP5_Very_Strong
The NM_002437.5(MPV17):c.186+2T>C variant causes a splice donor change. The variant allele was found at a frequency of 0.000018 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
MPV17
NM_002437.5 splice_donor
NM_002437.5 splice_donor
Scores
4
2
1
Splicing: ADA: 0.9912
1
1
Clinical Significance
Conservation
PhyloP100: 6.42
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 19 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
PP5
?
Variant 2-27312992-A-G is Pathogenic according to our data. Variant chr2-27312992-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38347.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.186+2T>C | splice_donor_variant | ENST00000380044.6 | |||
MPV17 | XM_005264326.5 | c.186+2T>C | splice_donor_variant | ||||
MPV17 | XM_017004151.2 | c.138+2T>C | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MPV17 | ENST00000380044.6 | c.186+2T>C | splice_donor_variant | 1 | NM_002437.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000112 AC: 17AN: 152210Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251484Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135916
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461846Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727224
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GnomAD4 genome ? AF: 0.000112 AC: 17AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74358
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 23, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change affects a donor splice site in intron 3 of the MPV17 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MPV17 are known to be pathogenic (PMID: 23714749). This variant is present in population databases (rs147952488, gnomAD 0.03%). Disruption of this splice site has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 20074988). ClinVar contains an entry for this variant (Variation ID: 38347). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 09, 2020 | Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29318572, 23137571, 29282788, 22593919, 20074988) - |
Mitochondrial DNA depletion syndrome 6 (hepatocerebral type) Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | May 24, 2019 | This variant affects the canonical splice donor site of intron 3 of 7, and is therefore predicted to interfere with splicing and result in loss of normal protein function. This variant has been previously reported as a compound heterozygous change in patients with hepatocerebral mitochondrial DNA depletion syndrome (PMID: 20074988), and has been classified as Pathogenic by another clinical diagnostic laboratory in the ClinVar database (Variation ID: 38347). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (8/277190) and thus is presumed to be rare. Multiple splice prediction tools suggest this variant is likely to interfere with normal splicing. Based on the available evidence, the c.186+2T>C variant is classified as Pathogenic. - |
Charcot-Marie-Tooth disease, axonal, type 2EE Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 08, 2024 | - - |
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
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at