chr11-47337453-T-G
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_000256.3(MYBPC3):āc.2540A>Cā(p.Tyr847Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y847H) has been classified as Pathogenic.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.2540A>C | p.Tyr847Ser | missense_variant | 25/35 | ENST00000545968.6 | NP_000247.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.2540A>C | p.Tyr847Ser | missense_variant | 25/35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
MYBPC3 | ENST00000399249.6 | c.2540A>C | p.Tyr847Ser | missense_variant | 24/34 | 5 | ENSP00000382193.2 | |||
MYBPC3 | ENST00000544791.1 | n.*45A>C | non_coding_transcript_exon_variant | 25/27 | 5 | ENSP00000444259.1 | ||||
MYBPC3 | ENST00000544791.1 | n.*45A>C | 3_prime_UTR_variant | 25/27 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461088Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 726824
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 02, 2015 | This variant has not been published in the literature and is not present in population databases. A missense change affecting the same amino acid, p.Tyr847His, was found in patient with hypertrophic cardiomyopathy (PMID: 20021930). This patient also was compound heterozygous for a second variant in MYBPC3, p.Gly523Arg, so the clinical significance of this observation is uncertain. In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This sequence change replaces tyrosine with serine at codon 847 of the MYBPC3 protein (p.Tyr847Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and serine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at