rs571457875
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_000256.3(MYBPC3):c.3190+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000563 in 1,599,838 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000056 ( 2 hom. )
Consequence
MYBPC3
NM_000256.3 splice_donor_region, intron
NM_000256.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.04145
2
Clinical Significance
Conservation
PhyloP100: -0.0980
Genes affected
MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.72).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.3190+4C>T | splice_donor_region_variant, intron_variant | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.3190+4C>T | splice_donor_region_variant, intron_variant | 5 | NM_000256.3 | P4 | |||
MYBPC3 | ENST00000399249.6 | c.3190+4C>T | splice_donor_region_variant, intron_variant | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152236Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000963 AC: 23AN: 238768Hom.: 0 AF XY: 0.000115 AC XY: 15AN XY: 130294
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GnomAD4 exome AF: 0.0000560 AC: 81AN: 1447484Hom.: 2 Cov.: 33 AF XY: 0.0000708 AC XY: 51AN XY: 720474
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GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152354Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74500
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 28, 2015 | The c.3190+4C>T variant in MYBPC3 has not been previously reported in individual s with cardiomyopathy, but has been identified in 9/16308 South Asian chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs571457875). This variant is located in the 5' splice region. Computational tools do not suggest an impact to splicing. However, this information is not pre dictive enough to rule out pathogenicity. In summary, the clinical significance of the c.3190+4C>T variant is uncertain. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 19, 2020 | Variant summary: MYBPC3 c.3190+4C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. Experimental evidence supports these predictions demonstrating the variant does not cause significantly altered splicing in a cell-based minigene assay (Ito_2017). The variant allele was found at a frequency of 9.6e-05 in 238768 control chromosomes, predominantly at a frequency of 0.00059 within the South Asian subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in MYBPC3 causing Cardiomyopathy (0.00059 vs 0.001), allowing no conclusion about variant significance. c.3190+4C>T has been reported in the literature in individuals affected with Cardiomyopathy (e.g. Headrick_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. A co-occurrence with a pathogenic variant has been reported (MYBPC3 c.3330+5G>C; Internal testing). Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance while one ClinVar submitter (evaluation after 2014) cites it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Cardiomyopathy Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 24, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 23, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 27, 2023 | In silico analysis supports that this variant does not alter splicing; Reported in an individual with cardiomyopathy in published literature who harbored additional cardiogenetic variants (Headrick et al., 2019); This variant is associated with the following publications: (PMID: 28679633, 29121657, 30985088) - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 13, 2023 | This sequence change falls in intron 29 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs571457875, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 29121657). ClinVar contains an entry for this variant (Variation ID: 181003). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 28679633). 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 16, 2021 | The c.3190+4C>T intronic variant results from a C to T substitution 4 nucleotides after coding exon 29 in the MYBPC3 gene. This variant was reported in an exome cohort, where it was seen in a pediatric dilated cardiomyopathy case who also had PKP2 and TTN variants detected (Headrick AT et al. Mol Genet Genomic Med, 2019 06;7:e593). Minigene assay results did not demonstrate a statistically significant splicing impact (Ito K et al. Proc Natl Acad Sci U S A, 2017 07;114:7689-7694). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at