rs11570058

chr11-47347892-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000256.3(MYBPC3):c.786C>T(p.Thr262=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,571,980 control chromosomes in the GnomAD database, including 11,203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (712 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10491 hom.)
• Consequence: MYBPC3 NM_000256.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -3.72

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-47347892-G-A is Benign according to our data. Variant chr11-47347892-G-A is described in ClinVar as [Benign]. Clinvar id is 42793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47347892-G-A is described in Lovd as [Benign]. Variant chr11-47347892-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.72 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.786C>T	p.Thr262=	synonymous_variant	7/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.786C>T	p.Thr262=	synonymous_variant	7/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.786C>T	p.Thr262=	synonymous_variant	7/34	5		A2
MYBPC3	ENST00000544791.1	c.786C>T	p.Thr262=	synonymous_variant, NMD_transcript_variant	7/27	5

Frequencies

GnomAD3 genomes AF: 0.0882 AC: 13420 AN: 152104 Hom.: 712 Cov.: 32

Gnomad AFR AF: 0.0408

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.0732

Gnomad ASJ AF: 0.0951

Gnomad EAS AF: 0.0177

Gnomad SAS AF: 0.0577

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.0808

GnomAD3 exomes AF: 0.0900 AC: 16455 AN: 182798 Hom.: 919 AF XY: 0.0909 AC XY: 8926 AN XY: 98182

Gnomad AFR exome AF: 0.0422

Gnomad AMR exome AF: 0.0456

Gnomad ASJ exome AF: 0.0918

Gnomad EAS exome AF: 0.0158

Gnomad SAS exome AF: 0.0666

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.116 AC: 165395 AN: 1419758 Hom.: 10491 Cov.: 34 AF XY: 0.115 AC XY: 80694 AN XY: 702194

Gnomad4 AFR exome AF: 0.0380

Gnomad4 AMR exome AF: 0.0484

Gnomad4 ASJ exome AF: 0.0950

Gnomad4 EAS exome AF: 0.0115

Gnomad4 SAS exome AF: 0.0676

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.129

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.0881 AC: 13418 AN: 152222 Hom.: 712 Cov.: 32 AF XY: 0.0858 AC XY: 6387 AN XY: 74420

Gnomad4 AFR AF: 0.0407

Gnomad4 AMR AF: 0.0730

Gnomad4 ASJ AF: 0.0951

Gnomad4 EAS AF: 0.0178

Gnomad4 SAS AF: 0.0580

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.124

Gnomad4 OTH AF: 0.0799

Alfa AF: 0.112 Hom.: 1402

Bravo AF: 0.0830

Asia WGS AF: 0.0400 AC: 139 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 18, 2008	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hypertrophic cardiomyopathy 4 Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Hypertrophic cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -

Left ventricular noncompaction 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 16, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2015

This alteration is classified as 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	-0.83
Cadd	Benign	0.23
Dann	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs11570058; hg19: chr11-47369443; COSMIC: COSV57027046;