6-49453643-G-T
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000255.4(MMUT):c.1025C>A(p.Ser342Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000205 in 1,460,966 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
MMUT
NM_000255.4 stop_gained
NM_000255.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 6.32
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 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 6-49453643-G-T is Pathogenic according to our data. Variant chr6-49453643-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 495777.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.1025C>A | p.Ser342Ter | stop_gained | 5/13 | ENST00000274813.4 | |
MMUT | XM_005249143.4 | c.1025C>A | p.Ser342Ter | stop_gained | 5/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMUT | ENST00000274813.4 | c.1025C>A | p.Ser342Ter | stop_gained | 5/13 | 1 | NM_000255.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251246Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135792
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GnomAD4 exome AF: 0.0000205 AC: 30AN: 1460966Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12AN XY: 726850
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | This sequence change creates a premature translational stop signal (p.Ser342*) in the MUT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). This variant is present in population databases (rs770466993, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with MUT-related conditions (PMID: 15643616, 19375370). ClinVar contains an entry for this variant (Variation ID: 495777). For these reasons, this variant has been classified as Pathogenic. - |
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 03, 2017 | - - |
Methylmalonic acidemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 26, 2017 | Variant summary: The MUT c.1025C>A (p.Ser342X) variant results in a premature termination codon, predicted to cause a truncated or absent MUT protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One truncation downstream of this position has been classified as pathogenic by our laboratory (e.g. c.1399C>T, p.Arg467X). One in silico tool predicts a damaging outcome for this variant. The variant of interest has been found in a large, broad control population, ExAC in 1/121004 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUT variant (0.0024152). This variant was found in methylmalonic acidemia patients in compound heterozigosity with other pathogenic variants such as MUT c.2080C>T, p.Arg694Trp and c.572C>A, p.Ala191Glu (Acquaviva_HumMut_2005, Nizon_Orph J Rare Dis_2013). Taken together, this variant is classified as pathogenic. - |
Computational scores
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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
Vest4
GERP RS
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