rs193922382

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_000256.3(MYBPC3):c.2914C>T(p.Arg972Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000176 in 1,576,500 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. R972Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 3.78

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011862069).

BP6

Variant 11-47334002-G-A is Benign according to our data. Variant chr11-47334002-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47334002-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.2914C>T	p.Arg972Trp	missense_variant	28/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.2914C>T	p.Arg972Trp	missense_variant	28/35	5	NM_000256.3	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.2914C>T	p.Arg972Trp	missense_variant	27/34	5		A2

Frequencies

GnomAD3 genomes

AF:

0.000867

AC:

132

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00299

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000226

AC:

AN:

185800

Hom.:

AF XY:

0.000219

AC XY:

AN XY:

100236

show subpopulations

Gnomad AFR exome

AF:

0.00371

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000127

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000101

AC:

144

AN:

1424154

Hom.:

Cov.:

AF XY:

0.0000752

AC XY:

AN XY:

705094

show subpopulations

Gnomad4 AFR exome

AF:

0.00318

Gnomad4 AMR exome

AF:

0.0000766

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000284

Gnomad4 OTH exome

AF:

0.000102

GnomAD4 genome

AF:

0.000873

AC:

133

AN:

152346

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00298

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000170

Hom.:

Bravo

AF:

0.000960

ESP6500AA

AF:

0.00290

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000185

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely 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	GeneDx	Apr 29, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22958901) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 03, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 02, 2023	Variant summary: MYBPC3 c.2914C>T (p.Arg972Trp) results in a non-conservative amino acid change located in the Immunoglobulin-like domain (IPR007110) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 185800 control chromosomes, predominantly at a frequency of 0.0037 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.7-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2914C>T has been reported in the literature in individuals affected with Cardiomyopathy without strong evidence of causality (Bick_2012, Burstein_2021). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22958901, 32746448). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 23, 2022	The p.Arg972Trp variant in MYBPC3 is classified as benign because it has been identified in 0.3% (58/18682) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). In addition, one mammalian species (elephant) carries a tryptophan at this position, despite high nearby amino acid conservation, further supporting a benign role. ACMG/AMP Criteria applied: BA1. -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 03, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 30, 2018	- -

Hypertrophic cardiomyopathy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2018

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

0.25

CardioboostCm

Benign

0.021

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;T;T

Eigen

Benign

-0.0024

Eigen_PC

Benign

0.089

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.1

M;.;.

MutationTaster

Benign

0.96

D;D;D

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-4.5

D;.;D

REVEL

Benign

0.11

Sift

Uncertain

0.021

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.26

MVP

0.72

MPC

0.23

ClinPred

0.078

GERP RS

3.1

Varity_R

0.21

gMVP

0.66

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