rs202189863
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_015506.3(MMACHC):c.641G>A(p.Arg214His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,614,138 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R214R) has been classified as Likely benign.
Frequency
Consequence
NM_015506.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMACHC | NM_015506.3 | c.641G>A | p.Arg214His | missense_variant | 4/4 | ENST00000401061.9 | |
MMACHC | NM_001330540.2 | c.470G>A | p.Arg157His | missense_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMACHC | ENST00000401061.9 | c.641G>A | p.Arg214His | missense_variant | 4/4 | 2 | NM_015506.3 | P1 | |
MMACHC | ENST00000616135.1 | c.470G>A | p.Arg157His | missense_variant | 4/5 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000118 AC: 18AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000164 AC: 41AN: 249494Hom.: 0 AF XY: 0.000163 AC XY: 22AN XY: 135352
GnomAD4 exome AF: 0.000241 AC: 353AN: 1461876Hom.: 1 Cov.: 31 AF XY: 0.000226 AC XY: 164AN XY: 727242
GnomAD4 genome ? AF: 0.000112 AC: 17AN: 152262Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74448
ClinVar
Submissions by phenotype
Cobalamin C disease Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 19, 2022 | The MMACHC c.641G>A; p.Arg214His variant (rs202189863), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 496435). This variant is found in the general population with an overall allele frequency of 0.016% (44/280864 alleles) in the Genome Aggregation Database. The arginine at codon 214 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.460). Due to limited information, the clinical significance of this variant is uncertain at this time. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 06, 2021 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 26, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 17, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 214 of the MMACHC protein (p.Arg214His). This variant is present in population databases (rs202189863, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MMACHC-related conditions. ClinVar contains an entry for this variant (Variation ID: 496435). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Disorders of Intracellular Cobalamin Metabolism Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 25, 2016 | Variant summary: The c.641G>A variant affects a conserved nucleotide, resulting in amino acid change from Arg to His. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). 5/5 programs in Alamut predict that this variant does not affect normal splicing. This variant is found in 17/120988 control chromosomes at a frequency of 0.0001405, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0030542). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at