rs397515983
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate
The NM_000256.3(MYBPC3):c.2714G>A(p.Ser905Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000455 in 1,538,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. S905S) has been classified as Benign.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.2714G>A | p.Ser905Asn | missense_variant | 26/35 | ENST00000545968.6 | NP_000247.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.2714G>A | p.Ser905Asn | missense_variant | 26/35 | 5 | NM_000256.3 | ENSP00000442795 | P4 | |
MYBPC3 | ENST00000399249.6 | c.2714G>A | p.Ser905Asn | missense_variant | 25/34 | 5 | ENSP00000382193 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.*219G>A | 3_prime_UTR_variant, NMD_transcript_variant | 26/27 | 5 | ENSP00000444259 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.0000198 AC: 3AN: 151816Hom.: 0 AF XY: 0.0000244 AC XY: 2AN XY: 81806
GnomAD4 exome AF: 0.0000498 AC: 69AN: 1386564Hom.: 0 Cov.: 34 AF XY: 0.0000497 AC XY: 34AN XY: 683492
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 74342
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 10, 2023 | This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 905 of the MYBPC3 protein (p.Ser905Asn). This variant is present in population databases (rs397515983, gnomAD 0.005%). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 42654). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the fibronectin type 3 domain C7 of the MYBPC3 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the 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 3/148288 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 10, 2015 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 26, 2023 | This missense variant replaces serine with asparagine at codon 905 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYBPC3-related disorders in the literature. This variant has been identified in 3/151816 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 20, 2022 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 18, 2022 | The c.2714G>A (p.S905N) alteration is located in exon 26 (coding exon 26) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 2714, causing the serine (S) at amino acid position 905 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at