11-47331882-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PVS1PM2PP3_StrongPP5
The NM_000256.3(MYBPC3):c.3815-1G>A variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,124 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
MYBPC3
NM_000256.3 splice_acceptor
NM_000256.3 splice_acceptor
Scores
3
2
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 1.20
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 15 ACMG points.
PVS1
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.3, offset of 8, new splice context is: cctcttctgcaatgcctcAGtga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it 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 11-47331882-C-T is Pathogenic according to our data. Variant chr11-47331882-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42746.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=8, Uncertain_significance=1}. Variant chr11-47331882-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.3815-1G>A | splice_acceptor_variant | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.3815-1G>A | splice_acceptor_variant | 5 | NM_000256.3 | P4 | |||
MYBPC3 | ENST00000399249.6 | c.3815-1G>A | splice_acceptor_variant | 5 | A2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000412 AC: 1AN: 242650Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 131818
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GnomAD4 exome AF: 0.00000206 AC: 3AN: 1458124Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 724984
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GnomAD4 genome Cov.: 33
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:9Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2023 | This sequence change affects an acceptor splice site in intron 33 of the MYBPC3 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs397516044, gnomAD 0.007%). Disruption of this splice site has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 33673806; Invitae). ClinVar contains an entry for this variant (Variation ID: 42746). 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. 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 19, 2023 | This variant causes a G to A nucleotide substitution at the -1 position of intron 33 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. To our knowledge, protein functional studies have not been reported for this variant. This variant has been reported in at least fourteen individuals affected with hypertrophic cardiomyopathy including an affected family member (PMID: 25611685, 27532257, 33495596, 33495597, 33663232, 33673806; communication with external laboratories: ClinVar SCV000739990.4, SCV000208208.11). This variant has been identified in 1/242650 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 30, 2011 | The 3815-1G>A variant has not been previously reported or been identified by our laboratory. This variant is predicted to cause abnormal splicing because the nu cleotide substitution occurs in the highly conserved splice consensus sequence. Pathogenic splice variants in MYBPC3 are common in patients with HCM, which sup ports a disease causing role. - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 20, 2018 | The c.3815-1 G>A likely pathogenic variant in the MYBPC3 gene has previously been reported in association with HCM (Alfares et al., 2015; Walsh et al., 2017). This variant has also been observed in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. The c.3815-1 G>A variant destroys the canonical splice acceptor site in intron 33 and is predicted to cause skipping of exon 34, the last coding exon of the MYBPC3 gene. Skipping of exon 34 would result in the loss of 3 amino acid residues and the natural termination codon, ultimately leading to extension of the protein length by using non-coding exon 35. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. Other splice site variants in the MYBPC3 gene, and one downstream nonsense variant, have been reported in HGMD in association with HCM (Stenson et al., 2014). Furthermore, the c.3815-1 G>A variant is not observed at significant frequency in large population cohorts (Lek et al., 2016). - |
Pathogenic, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Primary familial hypertrophic cardiomyopathy Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Dec 07, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Dec 23, 2016 | - - |
Cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 01, 2023 | This variant causes a G to A nucleotide substitution at the -1 position of intron 33 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. To our knowledge, protein functional studies have not been reported for this variant. This variant has been reported in at least fourteen individuals affected with hypertrophic cardiomyopathy including an affected family member (PMID: 25611685, 27532257, 33495596, 33495597, 33663232, 33673806; communication with external laboratories: ClinVar SCV000739990.4, SCV000208208.11). This variant has been identified in 1/242650 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 01, 2021 | The c.3815-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 34 of the MYBPC3 gene. 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. This alteration occurs at the 3' terminus of the MYBPC3 gene, is not expected to trigger nonsense-mediated mRNAdecay, and results in a frameshift that is predicted to impact only the last 3 amino acids of the native protein, although it is also expected to elongate the translated protein. The exact functional effect of this alteration is unknown. This variant has been identified in patients with hypertrophic cardiomyopathy (HCM) (Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). 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. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 26, 2020 | Variant summary: MYBPC3 c.3815-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The potentially skipped exon (exon 34) only encodes the last 3 amino acids of the protein. Thus the consequence of skipping of exon 34 is not clear. The variant allele was found at a frequency of 4.1e-06 in 242650 control chromosomes. c.3815-1G>A has been reported in the literature in at least one individual affected with HCM (Alfares_2015). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Five laboratories classified this variant as pathogenic/likely pathogenic, however, the most recent submission classified this variant as VUS. Based on the evidence outlined above, the variant was classified as VUS. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Benign
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: -9
DS_AL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at