11-47351294-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000256.3(MYBPC3):c.237C>A(p.Tyr79Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y79Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000256.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.237C>A | p.Tyr79Ter | stop_gained | 2/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.237C>A | p.Tyr79Ter | stop_gained | 2/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.237C>A | p.Tyr79Ter | stop_gained | 2/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.237C>A | p.Tyr79Ter | stop_gained, NMD_transcript_variant | 2/27 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1418418Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 700890
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 14, 2017 | The Y79X (c.237 C>A) variant in the MYBPC3 gene has been reported in at least 3 individuals with confirmedhypertrophic cardiomyopathy (HCM) or who were referred for HCM gene testing (Kapplinger et al., 2014; Bos et al.,2014). This variant is predicted to cause loss of normal protein function either by protein truncation or nonsensemediatedmRNA decay. Other nonsense variants in the MYBPC3 gene, including a different nonsense variant at thesame residue (c.237 C>G), have been reported in Human Gene Mutation Database in association with HCM (Stensonet al., 2014), indicating that loss of function is a known disease mechanism. Finally, the Y79X (c.237 C>A) variantis not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome VariantServer). - |
Hypertrophic cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2019 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This particular variant has been reported in the literature in several unrelated individuals with hypertrophic cardiomyopathy (PMID: 23140321, 24510615). This sequence change creates a premature translational stop signal at codon 79 (p.Tyr79*) of the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at