11-47332974-C-T
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>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,218 control chromosomes in the GnomAD database, with no homozygous occurrence. 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
Consequence
NM_000256.3 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.3331-1G>A | splice_acceptor_variant | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.3331-1G>A | splice_acceptor_variant | 5 | NM_000256.3 | P4 | |||
MYBPC3 | ENST00000399249.6 | c.3331-1G>A | splice_acceptor_variant | 5 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1456218Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 723776
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 29, 2013 | The 3331-1G>A variant in MYBPC3 has now been identified by our laboratory in 2 i ndividuals with HCM, including 1 Caucasian individual and 1 individual of unspec ified ancestry. Data from large population studies is insufficient to assess the frequency of this variant. This variant occurs in the invariant region (+/- 1,2 ) of the splice consensus sequence and is predicted to cause altered splicing le ading to an abnormal or absent protein. Truncating variants in MYBPC3 are establ ished as pathogenic for HCM. In summary, this variant meets our criteria to be c lassified as pathogenic (http://pcpgm.partners.org/LMM). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 29, 2021 | 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. 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: 177742). Disruption of this splice site has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, 27600940, 28640247). 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. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 20, 2016 | The c.3331-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 31 of the MYBPC3 gene. Since alterations that disrupt the canonical splice acceptor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at