rs398123278
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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.91C>T(p.Arg31Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,628 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 (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
MMUT
NM_000255.4 stop_gained
NM_000255.4 stop_gained
Scores
1
3
3
Clinical Significance
Conservation
PhyloP100: 2.25
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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 338 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 6-49459376-G-A is Pathogenic according to our data. Variant chr6-49459376-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 92688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49459376-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMUT | NM_000255.4 | c.91C>T | p.Arg31Ter | stop_gained | 2/13 | ENST00000274813.4 | |
MMUT | XM_005249143.4 | c.91C>T | p.Arg31Ter | stop_gained | 2/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMUT | ENST00000274813.4 | c.91C>T | p.Arg31Ter | stop_gained | 2/13 | 1 | NM_000255.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152116Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250914Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135622
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GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461512Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727088
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 17, 2022 | - - |
not provided, no classification provided | literature only | GeneReviews | - | mut(0) enzymatic subtype when homozygous - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 02, 2017 | - - |
Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Feb 07, 2019 | ACMG codes: PVS1, PS3, PM2, PP5 - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2023 | This sequence change creates a premature translational stop signal (p.Arg31*) 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 (rs398123278, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency (PMID: 16281286, 16435223, 17410422). ClinVar contains an entry for this variant (Variation ID: 92688). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 07, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 19, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34930662, 35361390, 16281286, 25525159, 25959030, 16435223, 17410422, 31998365, 32754920, 33820958, 34668645, 27167370, 31622506, 36186952) - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | May 15, 2019 | ACMG classification criteria: PVS1, PM2, PP5 - |
Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 04, 2020 | - - |
Methylmalonic acidemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 07, 2018 | Variant summary: MUT c.91C>T (p.Arg31X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., p.Gly284X and p.Arg467X). The variant allele was found at a frequency of 1.8e-05 in 276662 control chromosomes. This frequency is not higher than expected for a pathogenic variant in MUT causing Methylmalonic Acidemia (1.8e-05 vs 0.0024), allowing no conclusion about variant significance. c.91C>T has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia as both a homozygous and compound heterozygous allele. These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence showing a significant reduction in the propionate incorporation compared to controls (Worgan_2006), suggesting that the methylmalonyl-CoA mutase enzyme is impaired or absent. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
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