11-47348438-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate
The NM_000256.3(MYBPC3):āc.758A>Gā(p.Asn253Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,611,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.758A>G | p.Asn253Ser | missense_variant | 6/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.758A>G | p.Asn253Ser | missense_variant | 6/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.758A>G | p.Asn253Ser | missense_variant | 6/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.758A>G | p.Asn253Ser | missense_variant, NMD_transcript_variant | 6/27 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152036Hom.: 0 Cov.: 30
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1459614Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 725990
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152036Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2AN XY: 74254
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 | Apr 09, 2013 | Variant classified as Uncertain Significance - Favor Benign. The Asn253Ser varia nt in MYBPC3 has not been reported in individuals with cardiomyopathy or in larg e population studies. Asparagine (Asn) at position 253 is not conserved in mamm als or evolutionarily distant species and the change to Serine (Ser) is present in four species (2 mammalian). The variant was predicted to be benign using a co mputational tool clinically validated by our laboratory. This tool's benign pred iction is estimated to be correct 89% of the time (Jordan 2011). Although this d ata supports that the Asn253Ser variant may be benign, additional studies are ne eded to fully assess its clinical significance. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 29, 2019 | This missense variant replaces asparagine with serine at codon 253 of the MYBPC3 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/31362 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 08, 2018 | This sequence change replaces asparagine with serine at codon 253 of the MYBPC3 protein (p.Asn253Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. A single experimental study showed that this missense change does not alter splicing (PMID: 28679633). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MYBPC3-related disease. ClinVar contains an entry for this variant (Variation ID: 164143). This variant is not present in population databases (ExAC no frequency). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at