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rs761477436

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.Gly284Ter) 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

Scores

5
1
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.57
Variant links:
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]

Genome browser will be placed here

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 UniProt
MMUTNM_000255.4 linkuse as main transcriptc.850G>T p.Gly284Ter stop_gained 4/13 ENST00000274813.4
MMUTXM_005249143.4 linkuse as main transcriptc.850G>T p.Gly284Ter stop_gained 4/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MMUTENST00000274813.4 linkuse as main transcriptc.850G>T p.Gly284Ter stop_gained 4/131 NM_000255.4 P1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152058
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251340
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135822
show subpopulations
Gnomad AFR exome
AF:
0.000246
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460936
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726862
show subpopulations
Gnomad4 AFR exome
AF:
0.0000897
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152058
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74260
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000971
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.0000247
AC:
3

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 submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 10, 2022- -
Pathogenic, criteria provided, single submitterclinical testingRady Children's Institute for Genomic Medicine, Rady Children's Hospital San DiegoNov 15, 2018This 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 submitterclinical testingCounsylSep 06, 2017- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityFeb 28, 2022- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMay 15, 2023The 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. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJul 17, 2023This 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 providedclinical testingNatera, Inc.Sep 20, 2021- -
Methylmalonic acidemia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 27, 2018Variant 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.66
Cadd
Pathogenic
39
Dann
Uncertain
0.99
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
MutationTaster
Benign
1.0
A
Vest4
0.98
GERP RS
5.5

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs761477436; hg19: chr6-49423854; COSMIC: COSV51280117; API