rs1555120911
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000256.3(MYBPC3):c.2737+4_2737+7del variant causes a splice donor 5th base, intron change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 30)
Consequence
MYBPC3
NM_000256.3 splice_donor_5th_base, intron
NM_000256.3 splice_donor_5th_base, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.94
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.2737+4_2737+7del | splice_donor_5th_base_variant, intron_variant | ENST00000545968.6 | NP_000247.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.2737+4_2737+7del | splice_donor_5th_base_variant, intron_variant | 5 | NM_000256.3 | ENSP00000442795 | P4 | |||
MYBPC3 | ENST00000399249.6 | c.2737+4_2737+7del | splice_donor_5th_base_variant, intron_variant | 5 | ENSP00000382193 | A2 | ||||
MYBPC3 | ENST00000544791.1 | c.*242+4_*242+7del | splice_donor_5th_base_variant, intron_variant, NMD_transcript_variant | 5 | ENSP00000444259 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD3 genomes
Cov.:
30
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 30
GnomAD4 genome
Cov.:
30
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 15, 2021 | 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 520349). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 21750094). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change falls in intron 26 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 27, 2019 | The c.2737+4_2737+7delAGTG intronic variant is located 4 nucleotides after exon 26 in the MYBPC3 gene. This variant results from a deletion of 4 nucleotides at positions c.2737+4 to c.2737+7. This alteration has been reported in a single patient from a hypertrophic cardiomyopathy cohort, but clinical details were limited (Waldmüller S et al. Eur. J. Heart Fail. 2011;13:1185-92). These nucleotide positions range from highly to well conserved in available vertebrate species. In addition, this alteration is predicted to abolish the native splice donor site by the BDGP in silico tool and to weaken the efficiency of the native splice donor site by the ESEfinder in silico tool; however direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 25
DS_DL_spliceai
Position offset: 8
Find out detailed SpliceAI scores and Pangolin per-transcript scores at