11-47347854-C-G

Position:

• chr11-47347854-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000256.3(MYBPC3):​c.821+3G>C variant causes a splice region, 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. 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: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYBPC3 NM_000256.3 splice_region, intron
• Scores: Splicing: ADA: 0.4113
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.214

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.821+3G>C		splice_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.821+3G>C		splice_region_variant, intron_variant		5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.821+3G>C		splice_region_variant, intron_variant		5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.821+3G>C		splice_region_variant, intron_variant		5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1412096 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 697762

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 05, 2013

Variant classified as Uncertain Significance - Favor Pathogenic. The 821+3G>C va riant in MYBPC3 has not been previously reported in individuals with cardiomyopa thy. Data from large population studies is insufficient to assess the frequency of this variant. However, another variant at this position, 821+3G>T, has been r eported in 1 individual with HCM and segregated with disease in 1 affected relat ive (Kassem 2013). This variant is located in the 5' splice region. Computationa l tools suggest an impact to splicing, but this information is not predictive en ough to determine pathogenicity conclusively. Although this data supports that t he 821+3G>C variant may be pathogenic, additional studies are needed to fully as sess its clinical significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 29, 2022

The c.821+3G>C intronic variant results from a G to C substitution 3 nucleotides after coding exon 7 in the MYBPC3 gene. This alteration has been reported in a subject with hypertrophic cardiomyopathy (HCM), who also carried a missense alteration in MYH7 (Kassem HSh et al. J Cardiovasc Transl Res, 2013 Feb;6:65-80). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	4.9
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.41
dbscSNV1_RF	Benign	0.45
SpliceAI score (max)		0.80		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.80		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503213; hg19: chr11-47369405; COSMIC: COSV57025081;