1-45508982-C-CG
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_015506.3(MMACHC):c.619dup(p.Asp207GlyfsTer38) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R206R) has been classified as Likely benign.
Frequency
Consequence
NM_015506.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMACHC | NM_015506.3 | c.619dup | p.Asp207GlyfsTer38 | frameshift_variant | 4/4 | ENST00000401061.9 | |
MMACHC | NM_001330540.2 | c.448dup | p.Asp150GlyfsTer38 | frameshift_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMACHC | ENST00000401061.9 | c.619dup | p.Asp207GlyfsTer38 | frameshift_variant | 4/4 | 2 | NM_015506.3 | P1 | |
MMACHC | ENST00000616135.1 | c.448dup | p.Asp150GlyfsTer38 | frameshift_variant | 4/5 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249530Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135378
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461882Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 727244
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74350
ClinVar
Submissions by phenotype
Cobalamin C disease Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 21, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change creates a premature translational stop signal (p.Asp207Glyfs*38) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 76 amino acid(s) of the MMACHC protein. This variant is present in population databases (rs765913293, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with cobalamin C deficiency (PMID: 26270766). ClinVar contains an entry for this variant (Variation ID: 553035). This variant disrupts a region of the MMACHC protein in which other variant(s) (p.Tyr222*) have been determined to be pathogenic (PMID: 16311595, 19767224, 30157807). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 09, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 18, 2021 | NM_015506.2(MMACHC):c.619dupG(D207Gfs*38) is a frameshifting truncation variant classified as likely pathogenic in the context of methylmalonic aciduria and homocystinuria, cblC type. D207Gfs*38 has been observed in cases with relevant disease (PMID: 26825575). Functional assessments of this variant are not available in the literature. D207Gfs*38 has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_015506.2(MMACHC):c.619dupG(D207Gfs*38) is a frameshifting truncation variant in a gene where loss of function is a known mechanism of disease and is predicted to disrupt protein function. Please note: this variant was assessed in the context of healthy population screening. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 05, 2021 | Frameshift variant predicted to result in protein truncation, as the last 76 amino acids are replaced with 37 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26825575, 26270766, 31589614) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at