rs397516081

Variant names:

• chr11-47346623-T-C
• rs397516081
• NM_000256.3:c.926+4A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000256.3(MYBPC3):​c.926+4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,431,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 splice_region, intron
• Scores: Splicing: ADA: 0.4652
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.82
• Publications: 1 publications found

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]

MYBPC3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.926+4A>G		splice_region_variant, intron_variant	Intron 11 of 34	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.926+4A>G		splice_region_variant, intron_variant	Intron 11 of 34	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.926+4A>G		splice_region_variant, intron_variant	Intron 10 of 33	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.926+4A>G		splice_region_variant, intron_variant	Intron 11 of 26	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 228250 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1431830 Hom.: 0 Cov.: 38 AF XY: 0.00000141 AC XY: 1 AN XY: 709186

African (AFR) AF: 0.00 AC: 0 AN: 32450

American (AMR) AF: 0.00 AC: 0 AN: 40774

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24324

East Asian (EAS) AF: 0.00 AC: 0 AN: 39184

South Asian (SAS) AF: 0.0000241 AC: 2 AN: 82874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5610

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095110

Other (OTH) AF: 0.00 AC: 0 AN: 58912

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Oct 10, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.926+4A>G variant in MYBPC3 has been reported in one individual with dilated cardiomyopathy (DCM; Ito 2017 PMID: 28679633) and was absent from large population studies. This variant is located in the 5' splice region. Computational tools predict a splicing impact and functional studies using a cell-based minigene splicing assay provide some evidence that this variant impacts splicing (Ito 2017 PMID: 28679633). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS3_Supporting. -

not provided Uncertain:1

Oct 02, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with cardiomyopathy (Ito et al., 2017); however, additional clinical information was not provided; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 28679633) -

Hypertrophic cardiomyopathy Uncertain:1

Aug 12, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. It affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs397516081, ExAC 0.009%). This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 28679633). ClinVar contains an entry for this variant (Variation ID: 42803). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (PMID: 28679633). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.64
PhyloP100		1.8
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.47
dbscSNV1_RF	Benign	0.44
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.36		Position offset: 4

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

Other links and lift over

dbSNP: rs397516081; hg19: chr11-47368174;