rs193068692

Positions:

chr11-47350041-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1PM5BP4_StrongBP6BS2

The NM_000256.3(MYBPC3):c.478C>T(p.Arg160Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000391 in 1,562,838 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R160G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00038 ( 2 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:12

Conservation

PhyloP100: 2.81

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 Likely_benign. Variant got -5 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

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-47350041-G-C is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.010161191).

BP6

Variant 11-47350041-G-A is Benign according to our data. Variant chr11-47350041-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161311.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=6, Uncertain_significance=2}. Variant chr11-47350041-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.478C>T	p.Arg160Trp	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 linkuse as main transcript	c.478C>T	p.Arg160Trp	missense_variant	4/35	5	NM_000256.3	ENSP00000442795	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.478C>T	p.Arg160Trp	missense_variant	4/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.478C>T	p.Arg160Trp	missense_variant, NMD_transcript_variant	4/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000965

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00167

AC:

288

AN:

172746

Hom.:

AF XY:

0.00131

AC XY:

121

AN XY:

92158

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0100

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000244

Gnomad SAS exome

AF:

0.000255

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000849

Gnomad OTH exome

AF:

0.00170

GnomAD4 exome

AF:

0.000381

AC:

538

AN:

1410644

Hom.:

Cov.:

AF XY:

0.000326

AC XY:

227

AN XY:

697026

show subpopulations

Gnomad4 AFR exome

AF:

0.0000312

Gnomad4 AMR exome

AF:

0.00833

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00189

Gnomad4 SAS exome

AF:

0.000300

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000110

Gnomad4 OTH exome

AF:

0.000240

GnomAD4 genome

AF:

0.000480

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00359

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000967

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.000994

ESP6500AA

AF:

0.000247

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.000810

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 01, 2014	The Arg160Trp variant has been identified in one Japanese proband with late-onse t sporadic HCM and was absent from 200 control chromosomes (Anan 2007). However, the variant has now been identified by our laboratory in 8 individuals (4 DCM, HCM) 4 of whom (1 DCM, 3 HCM) carried a second variant which could be responsibl e for disease. Because HCM and DCM are caused by different defects at the cellul ar level, it is currently believed that the same variant is unlikely to cause bo th cardiomyopathies. In addition, at least 3/8 probands are of minority races (2 Hispanic, 1 Asian, 3 unspecified, 2 white) suggesting this variant may be a ben ign variant more common to a racial subpopulation. In summary, the occurrence of the Arg160Trp variant in HCM as well as DCM probands, its frequent presence wit h additional variants, and identification in minority races argues against a hig hly penetrant pathogenic role. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 10, 2018	Variant summary: MYBPC3 c.478C>T (p.Arg160Trp) results in a non-conservative amino acid change located in one of the Immunoglobulin-like domains (IPR007110) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 200008 control chromosomes, predominantly within the Latino subpopulation at a frequency of 0.0099 in the gnomAD database, including 2 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 10-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. The variant, c.478C>T, has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy, however these data do not allow any conclusion about variant significance. Moreover, co-occurrences with other pathogenic MYBPC3 variants have been reported (e.g. Zou2013: c.2308+1G>C and c.3137delC (T1046fs); Fourey 2017: c.109G>T (p.Gly37ter)), providing supporting evidence for a benign role. In one HCM family lack of co-segregation with the disease was also reported (Kadota 2015). One functional study reported that the variant does not cause aberrant splicing (Ito 2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign x4, likely benign x2, VUS x1). Based on the evidence outlined above, the variant was classified as benign. -

Cardiomyopathy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 06, 2022	- -

Hypertrophic cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Apr 05, 2018	- -

Dilated cardiomyopathy 1A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

May 05, 2015

- -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

Left ventricular noncompaction 10

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 26, 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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

MYBPC3: BS2 -

Hypertrophic cardiomyopathy 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 26, 2018

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2017

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

Uncertain

0.55

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.68

D;T;T

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.088

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.97

D;D;D

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.9

L;.;.

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-5.0

D;D;D

REVEL

Uncertain

0.60

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.86

MVP

0.88

MPC

0.84

ClinPred

0.088

GERP RS

1.5

Varity_R

0.45

gMVP

0.77

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