11-47346380-G-T

Position:

• chr11-47346380-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.927-10C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPC3 NM_000256.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.4436
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -2.84

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47346380-G-T is Pathogenic according to our data. Variant chr11-47346380-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42805.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.927-10C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.927-10C>A		splice_polypyrimidine_tract_variant, intron_variant		5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.927-10C>A		splice_polypyrimidine_tract_variant, intron_variant		5		A2
MYBPC3	ENST00000544791.1	c.927-10C>A		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 31, 2019	The c.927-10C>A variant in MYBPC3 has been identified in 3 individuals with HCM and segregated with disease in 4 affected relatives from 2 families (LMM data). It was absent from large population studies. This variant is located in the 3' splice region. An in vitro splicing assay demonstrates that this variant impacts splicing (Ito 2017). Variants that impact splicing and other loss-of-function variants in MYBPC3 are a common cause of HCM. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS3_Moderate, PM2, PS4_Supporting, PP1. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 24, 2023	This variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25611685). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 11 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. ClinVar contains an entry for this variant (Variation ID: 42805). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 28679633). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.013
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.44
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.45		Position offset: -10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201078659; hg19: chr11-47367931;