rs35078470

Positions:

chr11-47335928-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000256.3(MYBPC3):c.2686G>A(p.Val896Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00554 in 1,553,518 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. V896G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0057 ( 8 hom., cov: 30)

Exomes 𝑓: 0.0055 ( 50 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24

Conservation

PhyloP100: 1.01

Variant links:

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]

MYBPC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008191198).

BP6

Variant 11-47335928-C-T is Benign according to our data. Variant chr11-47335928-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 42652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47335928-C-T is described in Lovd as [Benign]. Variant chr11-47335928-C-T is described in Lovd as [Likely_benign]. Variant chr11-47335928-C-T is described in Lovd as [Pathogenic]. Variant chr11-47335928-C-T is described in Lovd as [Likely_pathogenic].

BS2

High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.2686G>A	p.Val896Met	missense_variant	26/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.2686G>A	p.Val896Met	missense_variant	26/35	5	NM_000256.3	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.2686G>A	p.Val896Met	missense_variant	25/34	5		A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.*191G>A		3_prime_UTR_variant, NMD_transcript_variant	26/27	5

Frequencies

GnomAD3 genomes

AF:

0.00571

AC:

869

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0271

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00739

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00574

AC:

996

AN:

173634

Hom.:

AF XY:

0.00568

AC XY:

536

AN XY:

94428

show subpopulations

Gnomad AFR exome

AF:

0.00157

Gnomad AMR exome

AF:

0.000443

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000561

Gnomad FIN exome

AF:

0.0287

Gnomad NFE exome

AF:

0.00600

Gnomad OTH exome

AF:

0.00412

GnomAD4 exome

AF:

0.00553

AC:

7742

AN:

1401224

Hom.:

Cov.:

AF XY:

0.00552

AC XY:

3822

AN XY:

692280

show subpopulations

Gnomad4 AFR exome

AF:

0.000446

Gnomad4 AMR exome

AF:

0.000552

Gnomad4 ASJ exome

AF:

0.000162

Gnomad4 EAS exome

AF:

0.0000279

Gnomad4 SAS exome

AF:

0.000749

Gnomad4 FIN exome

AF:

0.0261

Gnomad4 NFE exome

AF:

0.00559

Gnomad4 OTH exome

AF:

0.00498

GnomAD4 genome

AF:

0.00571

AC:

869

AN:

152294

Hom.:

Cov.:

AF XY:

0.00629

AC XY:

468

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.00320

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0271

Gnomad4 NFE

AF:

0.00740

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00555

Hom.:

Bravo

AF:

0.00346

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.00151

AC:

ESP6500EA

AF:

0.00482

AC:

ExAC

AF:

0.00452

AC:

543

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:24

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 31, 2018	Variant summary: MYBPC3 c.2686G>A (p.Val896Met) results in a conservative amino acid change located in the Fibronectin type III of the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0064 in 203838 control chromosomes in the gnomAD database, including 16 homozygotes. The observed variant frequency is more than 6-fold above the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is benign. c.2686G>A has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy. These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants have been reported in multiple individuals tested at LCA (MYBPC3 c.2373dupG, p.Trp792fsX41; MYH7 c.428G>A, p.Arg143Gln), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 25, 2015	p.Val896Met in exon 26 of MYBPC3: This variant is not expected to have clinical significance because it has been identified in 10% (68/690) of Finnish chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs35078470). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 15, 2015	- -
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

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 08, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	MYBPC3: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27737317, 28798025, 27182706, 26332594, 26914223, 27153395, 25569433, 21310275, 25078086, 25637381, 10521296, 21472310, 12110947, 15010274, 25447171, 23299917, 22763267, 24888384, 24055113) -

Hypertrophic cardiomyopathy

Benign:3

Likely benign, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Mar 11, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -

Primary familial hypertrophic cardiomyopathy

Benign:3

Likely benign, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Blueprint Genetics	Jun 26, 2014	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Left ventricular noncompaction 10

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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 19, 2018

- -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 05, 2022

- -

Primary familial dilated cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2016

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. -

MYBPC3-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 24, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;T;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.16

LIST_S2

Uncertain

0.87

D;D;D

MetaRNN

Benign

0.0082

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;.;.

MutationTaster

Benign

0.97

N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.8

N;.;N

REVEL

Benign

0.21

Sift

Uncertain

0.026

D;.;D

Sift4G

Benign

0.069

T;T;T

Vest4

0.18

MVP

0.65

MPC

0.23

ClinPred

0.011

GERP RS

2.2

Varity_R

0.20

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over