rs370958401
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000256.3(MYBPC3):c.373G>T(p.Ala125Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000356 in 1,403,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A125T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.373G>T | p.Ala125Ser | missense_variant | 3/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.373G>T | p.Ala125Ser | missense_variant | 3/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.373G>T | p.Ala125Ser | missense_variant | 3/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.373G>T | p.Ala125Ser | missense_variant, NMD_transcript_variant | 3/27 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000356 AC: 5AN: 1403674Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1AN XY: 695470
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 13, 2015 | Variant classified as Uncertain Significance - Favor Benign. The p.Ala125Ser var iant in MYBPC3 has been identified by our laboratory in one individual with HCM and was present in 1/8418 European chromosomes screened by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs370958401). Alanine (A la) at position 125 is not conserved in evolution and the change to serine (Ser) was predicted to be benign using a computational tool clinically validated by o ur laboratory. This tool's benign prediction is estimated to be correct 89% of t he time (Jordan 2011). In summary, while the clinical significance of the p.Ala1 25Ser variant is uncertain, these data suggest that it is more likely to be beni gn. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Oct 05, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 04, 2021 | Reported in patients referred for hypertrophic cardiomyopathy (Walsh et al., 2017); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 42738; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257) - |
Primary familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Jun 26, 2017 | - - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 14, 2023 | Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 42738). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). This variant is present in population databases (rs370958401, gnomAD 0.007%). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 125 of the MYBPC3 protein (p.Ala125Ser). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at