11-47332891-C-T

Position:

chr11-47332891-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM5PP3BP4_StrongBP6_Very_StrongBS2

The NM_000256.3(MYBPC3):c.3413G>A(p.Arg1138His) variant causes a missense change. The variant allele was found at a frequency of 0.000529 in 1,608,202 control chromosomes in the GnomAD database, including 4 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. R1138P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 4 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2B:13

Conservation

PhyloP100: 5.82

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 -13 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-47332891-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42712.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=6}.

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.019530088).

BP6

Variant 11-47332891-C-T is Benign according to our data. Variant chr11-47332891-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 177689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47332891-C-T is described in Lovd as [Likely_benign]. Variant chr11-47332891-C-T is described in Lovd as [Pathogenic].

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.3413G>A	p.Arg1138His	missense_variant	31/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.3413G>A	p.Arg1138His	missense_variant	31/35	5	NM_000256.3	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.3413G>A	p.Arg1138His	missense_variant	30/34	5		A2

Frequencies

GnomAD3 genomes

AF:

0.000993

AC:

151

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0123

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00113

AC:

267

AN:

237226

Hom.:

AF XY:

0.00109

AC XY:

140

AN XY:

128786

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000302

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000575

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0111

Gnomad NFE exome

AF:

0.000298

Gnomad OTH exome

AF:

0.000346

GnomAD4 exome

AF:

0.000481

AC:

700

AN:

1455950

Hom.:

Cov.:

AF XY:

0.000489

AC XY:

354

AN XY:

723628

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000457

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0105

Gnomad4 NFE exome

AF:

0.0000973

Gnomad4 OTH exome

AF:

0.000565

GnomAD4 genome

AF:

0.000992

AC:

151

AN:

152252

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

115

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0123

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000330

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000951

AC:

115

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2018	This variant is associated with the following publications: (PMID: 26332594, 22763267, 19150014, 21310275, 12110947, 22765922, 20800588, 29032884, 31006259) -

Cardiomyopathy

Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 13, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 13, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Dec 06, 2017	- -

Hypertrophic cardiomyopathy

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Uncertain significance, no assertion criteria provided	research	Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics	-	- -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 11, 2013

proposed classification - variant undergoing re-assessment, contact laboratory -

Hypertrophic cardiomyopathy 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Primary dilated cardiomyopathy

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Blueprint Genetics

Mar 25, 2014

- -

Primary familial hypertrophic cardiomyopathy

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Blueprint Genetics

Mar 25, 2014

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2019

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. -

Hypertrophic cardiomyopathy 1

Benign:1

Likely benign, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Mar 18, 2015

The MYBPC3 Arg1138His variant has been previously reported in both the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at a frequency of 0.017 (72 of 4168 in the European Finnish population), and at a frequency of 0.002 in the European sub-population of the 1000 genomes project (http://www.1000genomes.org/). We observed this variant in a single proband with typical HCM, presented 27 years and has no clear family history of disease. No other variants were identified. The variant has been reported in the literature (Jääskeläinen P, et al., 2002; García-Castro M, et al., 2009; Golbus JR, et al., 2012). Jääskeläinen et al. (2002) sequenced MYBPC3 in a Finnish HCM population and normal cohort, and identified this Arg1138His variant in multiple families (3 unrelated probands and 5 normal control samples). The variant does not co-segregate with disease and homozygous individuals did not express the HCM phenotype. Another report from Garcia-Castro et al. (2009) identified the Arg1138His variant in a single proband amongst a Spanish HCM population, however this proband is described as having no family history of disease and a concentric pattern of hypertrophy (IVS and PW 19mm). Arginine (Arg) at position 1138 is conserved across distantly related species, however the computational tool specifically designed to predict the effects of missense variants in HCM genes (Jordan DM, et al., 2011), cannot predict the outcome of this MYBPC3 Arg1138His variant. Due to the allele frequency of > 0.001 in population databases, and literature evidence, we classify this variant as "likely benign". -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.54

D;T;T

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

D;D;D

MetaRNN

Benign

0.020

T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.9

H;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-4.6

D;.;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0010

D;D;D

Vest4

0.97

MVP

0.95

MPC

0.93

ClinPred

0.31

GERP RS

5.4

Varity_R

0.68

gMVP

0.86

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