rs3729986

Positions:

• chr11-47350047-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000256.3(MYBPC3):​c.472G>A​(p.Val158Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0874 in 1,563,914 control chromosomes in the GnomAD database, including 6,739 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. V158V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.067 (436 hom., cov: 33)
  • Exomes 𝑓: 0.090 (6303 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.742

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 -18 ACMG points.

• PM1: In a domain Ig-like C2-type 1 (size 103) in uniprot entity MYPC3_HUMAN there are 30 pathogenic changes around while only 10 benign (75%) in NM_000256.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0020421147).
• BP6: Variant 11-47350047-C-T is Benign according to our data. Variant chr11-47350047-C-T is described in ClinVar as [Benign]. Clinvar id is 42758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47350047-C-T is described in Lovd as [Benign]. Variant chr11-47350047-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0981 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.472G>A	p.Val158Met	missense_variant	4/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.472G>A	p.Val158Met	missense_variant	4/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.472G>A	p.Val158Met	missense_variant	4/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.472G>A	p.Val158Met	missense_variant, NMD_transcript_variant	4/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes AF: 0.0675 AC: 10273 AN: 152132 Hom.: 436 Cov.: 33

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.0590

Gnomad ASJ AF: 0.0687

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0310

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.0621

GnomAD3 exomes AF: 0.0654 AC: 11428 AN: 174728 Hom.: 512 AF XY: 0.0651 AC XY: 6076 AN XY: 93288

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.0389

Gnomad ASJ exome AF: 0.0748

Gnomad EAS exome AF: 0.000321

Gnomad SAS exome AF: 0.0337

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.0938

Gnomad OTH exome AF: 0.0718

GnomAD4 exome AF: 0.0895 AC: 126407 AN: 1411664 Hom.: 6303 Cov.: 37 AF XY: 0.0881 AC XY: 61453 AN XY: 697578

Gnomad4 AFR exome AF: 0.0136

Gnomad4 AMR exome AF: 0.0412

Gnomad4 ASJ exome AF: 0.0700

Gnomad4 EAS exome AF: 0.000355

Gnomad4 SAS exome AF: 0.0350

Gnomad4 FIN exome AF: 0.105

Gnomad4 NFE exome AF: 0.101

Gnomad4 OTH exome AF: 0.0830

GnomAD4 genome AF: 0.0675 AC: 10273 AN: 152250 Hom.: 436 Cov.: 33 AF XY: 0.0665 AC XY: 4951 AN XY: 74458

Gnomad4 AFR AF: 0.0184

Gnomad4 AMR AF: 0.0590

Gnomad4 ASJ AF: 0.0687

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0313

Gnomad4 FIN AF: 0.100

Gnomad4 NFE AF: 0.100

Gnomad4 OTH AF: 0.0614

Alfa AF: 0.0878 Hom.: 857

Bravo AF: 0.0628

TwinsUK AF: 0.0941 AC: 349

ALSPAC AF: 0.104 AC: 401

ESP6500AA AF: 0.0171 AC: 69

ESP6500EA AF: 0.0864 AC: 718

ExAC AF: 0.0440 AC: 5121

Asia WGS AF: 0.0170 AC: 58 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Sep 09, 2019	- -
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+	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -

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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
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, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Nov 17, 2016	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2021	This variant is associated with the following publications: (PMID: 12818575, 25342278, 14563344, 20689143) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hypertrophic cardiomyopathy Benign:3

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

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

Apr 08, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 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
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T;T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.91	D;D;D
MetaRNN	Benign	0.0020	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	0.85	N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.82	P;.;.
Vest4		0.16
MPC		0.56
ClinPred		0.060	T
GERP RS		1.5
Varity_R		0.23
gMVP		0.40

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: rs3729986; hg19: chr11-47371598;