chr11-47350013-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5
The NM_000256.3(MYBPC3):c.505+1G>A variant causes a splice donor, intron change. 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000256.3 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.505+1G>A | splice_donor_variant, intron_variant | Intron 4 of 34 | 5 | NM_000256.3 | ENSP00000442795.1 | |||
MYBPC3 | ENST00000399249.6 | c.505+1G>A | splice_donor_variant, intron_variant | Intron 4 of 33 | 5 | ENSP00000382193.2 | ||||
MYBPC3 | ENST00000544791.1 | n.505+1G>A | splice_donor_variant, intron_variant | Intron 4 of 26 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1408074Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0AN XY: 695456
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Although the c.505+1 G>A mutation has not been reported as a disease - causing mutation or as a benign polymorphism to our knowledge, this mutation destroys the canonical splice donor site in intron 4 of the MYBPC3 gene and is predicted to cause abnormal gene splicing. The mutation is expected to lead to either an abnormal message that is subject to nonsense - mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site mutations in the MYBPC3 gene have been reported in association with HCM. The variant is found in HCM panel(s). -
Hypertrophic cardiomyopathy Pathogenic:1
Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with MYBPC3-related disease. ClinVar contains an entry for this variant (Variation ID: 181041). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 4 of the MYBPC3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. 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). 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. -
Cardiovascular phenotype Uncertain:1
The c.505+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 4 of the MYBPC3 gene. This alteration has been detected in hypertrophic cardiomyopathy (HCM) cohorts and in a sudden unexplained death cohort; however, clinical details were limited (Helms AS et al. Circ Genom Precis Med, 2020 10;13:396-405; Guo L et al. JAMA Cardiol. 2021 Sep;6(9):1013-1022; Sepp R et al. Diagnostics (Basel). 2022 May;12(5)). Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at