chr6-49448861-G-A
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000255.4(MMUT):c.1399C>T(p.Arg467*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000409 in 1,613,322 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
Consequence
NM_000255.4 stop_gained
Scores
Clinical Significance
Conservation
Publications
- methylmalonic aciduria due to methylmalonyl-CoA mutase deficiencyInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
- vitamin B12-unresponsive methylmalonic acidemia type mut-Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- vitamin B12-unresponsive methylmalonic acidemia type mut0Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MMUT | NM_000255.4 | c.1399C>T | p.Arg467* | stop_gained | Exon 7 of 13 | ENST00000274813.4 | NP_000246.2 | |
MMUT | XM_005249143.4 | c.1399C>T | p.Arg467* | stop_gained | Exon 7 of 13 | XP_005249200.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 151884Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000677 AC: 17AN: 251284 AF XY: 0.0000884 show subpopulations
GnomAD4 exome AF: 0.0000424 AC: 62AN: 1461438Hom.: 0 Cov.: 30 AF XY: 0.0000468 AC XY: 34AN XY: 727044 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000263 AC: 4AN: 151884Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74166 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:4
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The MUT c.1399C>T (p.Arg467Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. This variant has been described in five studies in eight probands with classic methylmalonic acidemia (MMA), with one in a homozygous state and seven in a compound heterozygous state (Peters et al. 2002; Acquaviva et al. 2005; Worgan et al. 2006; Dündar et al. 2012; Liu et al. 2012). The p.Arg467Ter variant was absent from 48 anonymous controls and is reported at a frequency of 0.001320 in the Ashkenazi Jewish population of the Genome Aggregation Database. Functional studies showed that six of the patients (one homozygote and five compound heterozygotes) carrying the p.Arg467Ter variant demonstrated zero enzyme activity ('mut0' phenotype) (Acquaviva et al. 2005). Based on the potential impact of truncating variants and presence in affected individuals, the p.Arg467Ter variant is classified as pathogenic for methylmalonic acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
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not provided Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg467*) 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 (rs774159791, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with methylmalonic acidemia (PMID: 12402345, 16281286, 22727635, 26790480). ClinVar contains an entry for this variant (Variation ID: 495778). For these reasons, this variant has been classified as Pathogenic. -
Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency Pathogenic:1
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Methylmalonic acidemia Pathogenic:1
Variant summary: The MUT c.1399C>T variant results into nonsense mutation in exon 7 predicted to cause a loss of protein function due to production of a truncated protein or nonsense-mediated mRNA decay. It was exclusively observed in the Non-Finnish European sub-cohort of the ExAC project at an allele frequency of 0.0015%, which does not exceed the maximal expected allele frequency of a disease-causing MUT allele (0.24%). In the literature, the variant was observed in several patients with methylmalonic aciduria in compound heterozygosity with other truncating as well as missense variants, consistent with a disease-causing nature. Two reputable databases as well as one clinical lab has classified this variant as pathogenic. Considering all evidence, the variant has been classified as a Disease Variant/Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at