11-47350008-A-G
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000256.3(MYBPC3):c.505+6T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,559,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
MYBPC3
NM_000256.3 splice_donor_region, intron
NM_000256.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.6378
2
Clinical Significance
Conservation
PhyloP100: 2.64
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 Likely_benign. Variant got -2 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MYBPC3 | NM_000256.3 | c.505+6T>C | splice_donor_region_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.505+6T>C | splice_donor_region_variant, intron_variant | 5 | NM_000256.3 | ENSP00000442795 | P4 | |||
| MYBPC3 | ENST00000399249.6 | c.505+6T>C | splice_donor_region_variant, intron_variant | 5 | ENSP00000382193 | A2 | ||||
| MYBPC3 | ENST00000544791.1 | c.505+6T>C | splice_donor_region_variant, intron_variant, NMD_transcript_variant | 5 | ENSP00000444259 |
Frequencies
GnomAD3 genomes 0.00000659 AC: 1AN: 151814Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000179 AC: 3AN: 167946Hom.: 0 AF XY: 0.0000112 AC XY: 1AN XY: 89474
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GnomAD4 exome AF: 0.0000213 AC: 30AN: 1408036Hom.: 0 Cov.: 37 AF XY: 0.0000115 AC XY: 8AN XY: 695400
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GnomAD4 genome 0.00000659 AC: 1AN: 151814Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74152
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 16, 2023 | This variant causes a T to C nucleotide substitution at the +6 position of intron 4 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYBPC3-related disorders in the literature. This variant has been identified in 3/167946 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Hypertrophic cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 28, 2023 | This variant causes a T to C nucleotide substitution at the +6 position of intron 4 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYBPC3-related disorders in the literature. This variant has been identified in 3/167946 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 16
Find out detailed SpliceAI scores and Pangolin per-transcript scores at