rs761477436
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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.850G>T(p.Gly284*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,994 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: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
MMUT
NM_000255.4 stop_gained
NM_000255.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.57
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 6-49456141-C-A is Pathogenic according to our data. Variant chr6-49456141-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 553762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MMUT | NM_000255.4 | c.850G>T | p.Gly284* | stop_gained | 4/13 | ENST00000274813.4 | NP_000246.2 | |
MMUT | XM_005249143.4 | c.850G>T | p.Gly284* | stop_gained | 4/13 | XP_005249200.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MMUT | ENST00000274813.4 | c.850G>T | p.Gly284* | stop_gained | 4/13 | 1 | NM_000255.4 | ENSP00000274813.3 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152058Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251340Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135822
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460936Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726862
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 152058Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74260
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Nov 15, 2018 | This nonsense variant found in exon 4 of 13 is predicted to result in loss of normal protein function. This variant has been previously reported as compound heterozygous change in patients with methylmalonic acidemia (PMID: 16281286). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0016% (4/251340) and thus is presumed to be rare. Based on the available evidence, the c.850G>T (p.Gly284Ter) variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 06, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 10, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 15, 2023 | The MMUT c.850G>T (p.Gly284Ter) nonsense variant results in the loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant was identified in trans with likely pathogenic and pathogenic variants in individuals with a phenotype consistent with methylmalonic aciduria (PMID: 16281286; 36007526). The p.Gly284Ter variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database and has been classified as pathogenic by at least three submitters in ClinVar. This variant was identified in trans with a likely pathogenic variant. Based on the available evidence, the c.850A>G (p.Gly284Ter) variant is classified as pathogenic for methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 28, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 17, 2023 | This premature translational stop signal has been observed in individual(s) with methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency (PMID: 16281286). This sequence change creates a premature translational stop signal (p.Gly284*) 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 (rs761477436, gnomAD 0.03%). ClinVar contains an entry for this variant (Variation ID: 553762). For these reasons, this variant has been classified as Pathogenic. - |
Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 20, 2021 | - - |
Methylmalonic acidemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 27, 2018 | Variant summary: MUT c.850G>T (p.Gly284X) 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. c.1025C>A (p.Ser342X) and c.1399C>T (p.Arg467X)). The variant was observed with an allele frequency of 1.6e-05 in 246108 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in MUT causing Methylmalonic Acidemia (1.6e-05 vs. 0.0024), allowing no conclusion about variant significance. The variant, c.850G>T, has been reported in the literature in individuals affected with Methylmalonic Acidemia (Worgan 2006). These data indicate that the variant may be associated with disease. This publication also reported experimental evidence evaluating an impact on protein function, with the most pronounced variant effect resulting 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
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
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