rs749264632
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_015506.3(MMACHC):βc.352delβ(p.Gln118ArgfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 0.0000055 ( 0 hom. )
Consequence
MMACHC
NM_015506.3 frameshift
NM_015506.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.87
Genes affected
MMACHC (HGNC:24525): (metabolism of cobalamin associated C) The exact function of the protein encoded by this gene is not known, however, its C-terminal region shows similarity to TonB, a bacterial protein involved in energy transduction for cobalamin (vitamin B12) uptake. Hence, it is postulated that this protein may have a role in the binding and intracellular trafficking of cobalamin. Mutations in this gene are associated with methylmalonic aciduria and homocystinuria type cblC. [provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 1-45508284-GC-G is Pathogenic according to our data. Variant chr1-45508284-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 439905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMACHC | NM_015506.3 | c.352del | p.Gln118ArgfsTer6 | frameshift_variant | 3/4 | ENST00000401061.9 | |
MMACHC | NM_001330540.2 | c.181del | p.Gln61ArgfsTer6 | frameshift_variant | 3/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMACHC | ENST00000401061.9 | c.352del | p.Gln118ArgfsTer6 | frameshift_variant | 3/4 | 2 | NM_015506.3 | P1 | |
MMACHC | ENST00000616135.1 | c.181del | p.Gln61ArgfsTer6 | frameshift_variant | 3/5 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000361 AC: 9AN: 249434Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135330
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461868Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727236
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cobalamin C disease Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 16, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 29, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 439905). This premature translational stop signal has been observed in individual(s) with methylmalonic aciduria and homocystinuria, although the second alleles in these individuals were not reported (PMID: 16311595). This variant is present in population databases (rs749264632, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Gln118Argfs*6) in the MMACHC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMACHC are known to be pathogenic (PMID: 16311595). - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 24, 2020 | Variant summary: MMACHC c.352delC (p.Gln118ArgfsX6) 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. The variant allele was found at a frequency of 3.6e-05 in 249434 control chromosomes (gnomAD). c.352delC has been reported in the literature in multiple compound heterozygous- (Lerner-Ellis_2006, Gilson_2018) and in at least one homozygous individuals (Bonafede_2015, Ahrens-Nicklas_2017) who were affected with Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 04, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 18, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 31, 2022 | - - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 17, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 09, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29379858, 28071971, 32746448, 32778825, 28151490, 26658511, 16311595) - |
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