rs727504305
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000256.3(MYBPC3):c.3331-1G>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
MYBPC3
NM_000256.3 splice_acceptor
NM_000256.3 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.56
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 Pathogenic. Variant got 22 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 11-47332974-C-G is Pathogenic according to our data. Variant chr11-47332974-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 519194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.3331-1G>C | splice_acceptor_variant | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.3331-1G>C | splice_acceptor_variant | 5 | NM_000256.3 | P4 | |||
MYBPC3 | ENST00000399249.6 | c.3331-1G>C | splice_acceptor_variant | 5 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 21, 2019 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 28640247). ClinVar contains an entry for this variant (Variation ID: 519194). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 30 of the MYBPC3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 12, 2024 | The c.3331-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide before coding exon 31 of the MYBPC3 gene. This variant has been detected in individuals with features consistent with hypertrophic cardiomyopathy (Ko C. Genet Med. 2018 Jan;20(1):69-75; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -4
DS_AL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at