NM_000255.4:c.2179C>T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000255.4(MMUT):c.2179C>T(p.Arg727*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000018 in 1,613,668 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
Consequence
NM_000255.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MMUT | NM_000255.4 | c.2179C>T | p.Arg727* | stop_gained | Exon 13 of 13 | ENST00000274813.4 | NP_000246.2 | |
MMUT | XM_005249143.4 | c.2179C>T | p.Arg727* | stop_gained | Exon 13 of 13 | XP_005249200.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152046Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251350Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135856
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461622Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 16AN XY: 727106
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152046Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74246
ClinVar
Submissions by phenotype
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:3Other:1
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mut(0) enzymatic subtype when homozygous -
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The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000218998 / PMID: 16281286). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided Pathogenic:3
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This sequence change creates a premature translational stop signal (p.Arg727*) in the MUT gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the MUT protein. This variant is present in population databases (rs779990936, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with methylmalonic acidemia (PMID: 16281286, 17075691, 17445044, 22727635, 26454439, 27489777). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 218998). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
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Methylmalonic acidemia Pathogenic:2
Variant summary: MUT c.2179C>T (p.Arg727X) 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. A truncation downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.2e-05 in 251350 control chromosomes (gnomAD). c.2179C>T has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (Worgan_2006, Sakamoto_2007, Chu_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
The p.Arg727X variant in MMUT has been reported, in the homozygous or compound heterozygous state, in several individuals affected with methylmalonic acidemia (Worgan 2006 PMID: 16281286, Oyama 2007 PMID: 17445044, Chu 2016 PMID: 27233228, Dündar 2012 PMID 22727635, Sakamoto 2007 PMID: 17075691, Han 2015 PMID: 26454439,Burlina 2016 PMID: 27489777). It has also been reported in ClinVar (Variation ID 218998) and it has been identified in 2/68004 European chromosomes by gnomADv. 3 (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination: codon at position 727. This alteration occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive methylmalonic acidemia. ACMG/AMP Criteria applied: PM2_Supporting, PVS1_Strong, PM3_VeryStrong. -
Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency Pathogenic:1
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Abnormality of metabolism/homeostasis Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at