rs727504858

chr11-47349789-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000256.3(MYBPC3):c.639C>T(p.Tyr213=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000089 in 1,606,848 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (2 hom.)
• Consequence: MYBPC3 NM_000256.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.118

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 11-47349789-G-A is Benign according to our data. Variant chr11-47349789-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 179421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.118 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.639C>T	p.Tyr213=	synonymous_variant	5/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.639C>T	p.Tyr213=	synonymous_variant	5/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.639C>T	p.Tyr213=	synonymous_variant	5/34	5		A2
MYBPC3	ENST00000544791.1	c.639C>T	p.Tyr213=	synonymous_variant, NMD_transcript_variant	5/27	5

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152216 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000165 AC: 40 AN: 241900 Hom.: 0 AF XY: 0.000197 AC XY: 26 AN XY: 132046

Gnomad AFR exome AF: 0.000133

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000502

Gnomad SAS exome AF: 0.000759

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000448

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000921 AC: 134 AN: 1454632 Hom.: 2 Cov.: 31 AF XY: 0.000122 AC XY: 88 AN XY: 723882

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.000895

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152216 Hom.: 1 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74364

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000620

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000586 Hom.: 0

Bravo AF: 0.0000680

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 06, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 21, 2023	- -

Hypertrophic cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 12, 2013

Tyr213Tyr in exon 5 of MYBPC3: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. Tyr213Tyr in exon 5 of MYBPC3 (allele frequ ency = n/a) -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 31, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 13, 2021

This variant is associated with the following publications: (PMID: 28679633) -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 15, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	3.6
Dann	Benign	0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs727504858; hg19: chr11-47371340; COSMIC: COSV57027065;