chr11-47332891-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. R1138C) has been classified as Uncertain significance.

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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: {Uncertain_significance=6, Likely_pathogenic=3}.

PP3

Multiple lines of computational evidence support a deleterious effect 9: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, PROVEAN, REVEL, 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 rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.3413G>A	p.Arg1138His	missense_variant	Exon 31 of 35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6 link	c.3413G>A	p.Arg1138His	missense_variant	Exon 31 of 35	5	NM_000256.3	ENSP00000442795.1		Q14896-1
MYBPC3	ENST00000399249.6 link	c.3413G>A	p.Arg1138His	missense_variant	Exon 30 of 34	5		ENSP00000382193.2		A8MXZ9

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

GnomAD2 exomes

AF:

0.00113

AC:

267

AN:

237226

AF XY:

0.00109

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 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

AC:

AN:

33402

Gnomad4 AMR exome

AF:

0.0000457

AC:

AN:

43746

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25960

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39526

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

84884

Gnomad4 FIN exome

AF:

0.0105

AC:

556

AN:

52882

Gnomad4 NFE exome

AF:

0.0000973

AC:

108

AN:

1109614

Gnomad4 Remaining exome

AF:

0.000565

AC:

AN:

60178

Heterozygous variant carriers

111

148

185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

AC:

0.0000963298

AN:

0.0000963298

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.0123

AC:

0.0123259

AN:

0.0123259

Gnomad4 NFE

AF:

0.000221

AC:

0.000220562

AN:

0.000220562

Gnomad4 OTH

AF:

0.000474

AC:

0.000474383

AN:

0.000474383

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000121

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

Aug 01, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26332594, 22763267, 19150014, 21310275, 12110947, 22765922, 20800588, 29032884, 31006259) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:3

Dec 06, 2017

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 13, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy

Uncertain:1Benign:1

Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Feb 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Primary dilated cardiomyopathy

Benign:1

Mar 25, 2014

Blueprint Genetics

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy 4

Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary familial hypertrophic cardiomyopathy

Benign:1

Mar 25, 2014

Blueprint Genetics

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 01, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Mar 18, 2015

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

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;.;.

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

Mutation Taster

=94/6

polymorphism

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