rs776473131
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_032601.4(MCEE):c.419delA(p.Lys140ArgfsTer6) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000267 in 1,612,086 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000053 ( 1 hom., cov: 31)
Exomes 𝑓: 0.000024 ( 0 hom. )
Consequence
MCEE
NM_032601.4 frameshift
NM_032601.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.23
Genes affected
MCEE (HGNC:16732): (methylmalonyl-CoA epimerase) The product of this gene catalyzes the interconversion of D- and L-methylmalonyl-CoA during the degradation of branched chain amino acids. odd chain-length fatty acids, and other metabolites. Mutations in this gene result in methylmalonyl-CoA epimerase deficiency, which is presented as mild to moderate methylmalonic aciduria. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.211 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MCEE | ENST00000244217.6 | c.419delA | p.Lys140ArgfsTer6 | frameshift_variant | Exon 3 of 3 | 1 | NM_032601.4 | ENSP00000244217.5 | ||
MCEE | ENST00000413592.5 | c.125delA | p.Lys42ArgfsTer6 | frameshift_variant | Exon 2 of 2 | 2 | ENSP00000391140.1 | |||
MCEE | ENST00000462609.2 | n.365delA | non_coding_transcript_exon_variant | Exon 5 of 5 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000527 AC: 8AN: 151896Hom.: 1 Cov.: 31
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GnomAD3 exomes AF: 0.0000360 AC: 9AN: 250236Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135320
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GnomAD4 exome AF: 0.0000240 AC: 35AN: 1460190Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 18AN XY: 726446
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GnomAD4 genome AF: 0.0000527 AC: 8AN: 151896Hom.: 1 Cov.: 31 AF XY: 0.0000539 AC XY: 4AN XY: 74190
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 14, 2024 | Variant summary: MCEE c.419delA (p.Lys140ArgfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. The variant allele was found at a frequency of 3.6e-05 in 250236 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.419delA has been reported in the literature in at least one individual affected with Parkinson disease, dementia, stroke and elevated levels of methylmalonic acid (e.g., Andrasson_2019). While the current variant may not result in NMD, it alters several amino acids located in the Vicinal oxygen chelate (VOC) domain. It is unclear what impact the variant will have on the function of this protein. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31146325). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
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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