rs879253851
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000255.4(MMUT):c.2194_2197delinsTGGAA(p.Ala732TrpfsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A732A) has been classified as Benign.
Frequency
Genomes: not found (cov: 32)
Consequence
MMUT
NM_000255.4 frameshift
NM_000255.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.20
Genes affected
MMUT (HGNC:7526): (methylmalonyl-CoA mutase) This gene encodes the mitochondrial enzyme methylmalonyl Coenzyme A mutase. In humans, the product of this gene is a vitamin B12-dependent enzyme which catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA, while in other species this enzyme may have different functions. Mutations in this gene may lead to various types of methylmalonic aciduria. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 6-49431784-CGGC-TTCCA is Pathogenic according to our data. Variant chr6-49431784-CGGC-TTCCA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 222942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMUT | NM_000255.4 | c.2194_2197delinsTGGAA | p.Ala732TrpfsTer6 | frameshift_variant | 13/13 | ENST00000274813.4 | |
MMUT | XM_005249143.4 | c.2194_2197delinsTGGAA | p.Ala732TrpfsTer6 | frameshift_variant | 13/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMUT | ENST00000274813.4 | c.2194_2197delinsTGGAA | p.Ala732TrpfsTer6 | frameshift_variant | 13/13 | 1 | NM_000255.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | MMUT: PVS1, PM2, PS4:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 12, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant is also known as 2270del4/ins5 and c.2194-2197del4ins5 (p.Ala732fsX737). This premature translational stop signal has been observed in individual(s) with methylmalonic acidemia (PMID: 10923046, 16281286, 16435223, 27167370). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change creates a premature translational stop signal (p.Ala732Trpfs*6) in the MUT gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 19 amino acid(s) of the MUT protein. - |
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 08, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | University Children's Hospital, University of Zurich | - | - - |
Methylmalonic acidemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 27, 2018 | Variant summary: MUT c.2194_2197delinsTGGAA (p.Ala732TrpfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 246164 control chromosomes (gnomAD). c.2194_2197delinsTGGAA has been reported in the literature in individuals affected with Methylmalonic Acidemia (Cavicchi_2005, Forny_2016, Worgan_2006). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. No clinical diagnostic laboratories have submitted 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:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at