rs11570052

chr11-47349863-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000256.3(MYBPC3):c.565G>A(p.Val189Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,612,566 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V189D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (20 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 3.21

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010700673).
• BP6: Variant 11-47349863-C-T is Benign according to our data. Variant chr11-47349863-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 36614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47349863-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.565G>A	p.Val189Ile	missense_variant	5/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.565G>A	p.Val189Ile	missense_variant	5/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.565G>A	p.Val189Ile	missense_variant	5/34	5		A2
MYBPC3	ENST00000544791.1	c.565G>A	p.Val189Ile	missense_variant, NMD_transcript_variant	5/27	5

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 307 AN: 152258 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00351

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00260 AC: 637 AN: 245140 Hom.: 4 AF XY: 0.00296 AC XY: 395 AN XY: 133466

Gnomad AFR exome AF: 0.000202

Gnomad AMR exome AF: 0.00210

Gnomad ASJ exome AF: 0.00414

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00397

Gnomad FIN exome AF: 0.000430

Gnomad NFE exome AF: 0.00334

Gnomad OTH exome AF: 0.00353

GnomAD4 exome AF: 0.00257 AC: 3755 AN: 1460190 Hom.: 20 Cov.: 31 AF XY: 0.00270 AC XY: 1963 AN XY: 726326

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00227

Gnomad4 ASJ exome AF: 0.00441

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00383

Gnomad4 FIN exome AF: 0.000378

Gnomad4 NFE exome AF: 0.00262

Gnomad4 OTH exome AF: 0.00302

GnomAD4 genome AF: 0.00201 AC: 307 AN: 152376 Hom.: 1 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74518

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00285

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00336 Hom.: 2

Bravo AF: 0.00228

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000241 AC: 1

ESP6500EA AF: 0.00345 AC: 29

ExAC AF: 0.00256 AC: 310

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00431

EpiControl AF: 0.00428

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 20, 2016	reclassified based on 2015 re-review. Data from that re-review is summarized in DOI: 10.1161/CIRCGENETICS.116.001700. -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 22429680, 23861362, 24503780, 24721642, 25342278, 27483260, 21310275) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	MYBPC3: BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2023	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2015	p.Val189Ile in exon 5 of MYBPC3: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (204/60142) of European chrom osomes, including 2 homozygotes, by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs11570052). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 05, 2016	- -

Hypertrophic cardiomyopathy 4 Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 16, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 02, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2018	- -

Left ventricular noncompaction 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 16, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Nov 14, 2018

- -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Primary familial hypertrophic cardiomyopathy Benign:1

Benign, no assertion criteria provided

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 26, 2015

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 05, 2019

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
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;T
Eigen	Benign	-0.022
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.42	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.40	T;T;T
Sift4G	Benign	0.57	T;T;T
Polyphen		0.20	B;.;.
Vest4		0.28
MVP		0.69
MPC		0.23
ClinPred		0.10	T
GERP RS		4.8
Varity_R		0.12
gMVP		0.24

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: rs11570052; hg19: chr11-47371414;