rs11570051

Positions:

• chr11-47349891-G-A
• chr11-47349891-G-C

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.537C>T​(p.Ala179=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0481 in 1,609,356 control chromosomes in the GnomAD database, including 2,156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A179A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.039 (163 hom., cov: 32)
  • Exomes 𝑓: 0.049 (1993 hom.)
• Consequence: MYBPC3 NM_000256.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -2.97

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=-0.74).
• BP6: Variant 11-47349891-G-A is Benign according to our data. Variant chr11-47349891-G-A is described in ClinVar as [Benign]. Clinvar id is 42768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47349891-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.97 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0736 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.537C>T	p.Ala179=	synonymous_variant	5/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.537C>T	p.Ala179=	synonymous_variant	5/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.537C>T	p.Ala179=	synonymous_variant	5/34	5		A2
MYBPC3	ENST00000544791.1	c.537C>T	p.Ala179=	synonymous_variant, NMD_transcript_variant	5/27	5

Frequencies

GnomAD3 genomes AF: 0.0391 AC: 5948 AN: 152158 Hom.: 163 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.0774

Gnomad ASJ AF: 0.0571

Gnomad EAS AF: 0.00425

Gnomad SAS AF: 0.0268

Gnomad FIN AF: 0.0497

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0494

Gnomad OTH AF: 0.0378

GnomAD3 exomes AF: 0.0452 AC: 10759 AN: 238206 Hom.: 291 AF XY: 0.0439 AC XY: 5698 AN XY: 129906

Gnomad AFR exome AF: 0.00932

Gnomad AMR exome AF: 0.0825

Gnomad ASJ exome AF: 0.0515

Gnomad EAS exome AF: 0.00160

Gnomad SAS exome AF: 0.0273

Gnomad FIN exome AF: 0.0536

Gnomad NFE exome AF: 0.0481

Gnomad OTH exome AF: 0.0434

GnomAD4 exome AF: 0.0491 AC: 71504 AN: 1457080 Hom.: 1993 Cov.: 31 AF XY: 0.0480 AC XY: 34739 AN XY: 724430

Gnomad4 AFR exome AF: 0.00790

Gnomad4 AMR exome AF: 0.0829

Gnomad4 ASJ exome AF: 0.0528

Gnomad4 EAS exome AF: 0.00271

Gnomad4 SAS exome AF: 0.0281

Gnomad4 FIN exome AF: 0.0540

Gnomad4 NFE exome AF: 0.0524

Gnomad4 OTH exome AF: 0.0427

GnomAD4 genome AF: 0.0390 AC: 5944 AN: 152276 Hom.: 163 Cov.: 32 AF XY: 0.0399 AC XY: 2970 AN XY: 74448

Gnomad4 AFR AF: 0.0101

Gnomad4 AMR AF: 0.0772

Gnomad4 ASJ AF: 0.0571

Gnomad4 EAS AF: 0.00426

Gnomad4 SAS AF: 0.0266

Gnomad4 FIN AF: 0.0497

Gnomad4 NFE AF: 0.0495

Gnomad4 OTH AF: 0.0370

Alfa AF: 0.0453 Hom.: 82

Bravo AF: 0.0397

Asia WGS AF: 0.0200 AC: 69 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 18, 2008	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hypertrophic cardiomyopathy 4 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, 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	- -

Hypertrophic cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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 13, 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

Jun 16, 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	-0.74
CADD	Benign	0.0050
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs11570051; hg19: chr11-47371442;