rs3729799

chr11-47333743-G-Achr11-47333743-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM5 BP4_Strong BP6_Very_Strong BS2

The NM_000256.3(MYBPC3):c.3004C>T(p.Arg1002Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000375 in 1,599,242 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1002Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.56

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47333742-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.016332686).
• BP6: Variant 11-47333743-G-A is Benign according to our data. Variant chr11-47333743-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 42676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47333743-G-A is described in Lovd as [Benign]. Variant chr11-47333743-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.3004C>T	p.Arg1002Trp	missense_variant	29/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3004C>T	p.Arg1002Trp	missense_variant	29/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.3004C>T	p.Arg1002Trp	missense_variant	28/34	5		A2

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 290 AN: 152230 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00663

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000586 AC: 138 AN: 235510 Hom.: 0 AF XY: 0.000501 AC XY: 64 AN XY: 127690

Gnomad AFR exome AF: 0.00761

Gnomad AMR exome AF: 0.000266

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000391

Gnomad SAS exome AF: 0.0000706

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000278

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.000212 AC: 307 AN: 1446894 Hom.: 0 Cov.: 32 AF XY: 0.000185 AC XY: 133 AN XY: 718724

Gnomad4 AFR exome AF: 0.00695

Gnomad4 AMR exome AF: 0.000317

Gnomad4 ASJ exome AF: 0.0000396

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0000473

Gnomad4 FIN exome AF: 0.0000614

Gnomad4 NFE exome AF: 0.0000208

Gnomad4 OTH exome AF: 0.000351

GnomAD4 genome AF: 0.00192 AC: 292 AN: 152348 Hom.: 2 Cov.: 33 AF XY: 0.00185 AC XY: 138 AN XY: 74500

Gnomad4 AFR AF: 0.00666

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000425 Hom.: 1

Bravo AF: 0.00210

ESP6500AA AF: 0.00499 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000596 AC: 72

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2012	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 04, 2018	This variant is classified as benign because it has been identified in 0.7% (182 /23792) of African chromosomes including 2 homozygotes, by the genome Aggregatio n Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs3729799). ACMG/AM P Criteria applied: BA1. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Sep 26, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Jun 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 16, 2019	- -

not provided Benign:2

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 09, 2023	- -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
CardioboostCm	Uncertain	0.39
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.72	D
LIST_S2	Pathogenic	0.98	D;D;D
MetaRNN	Benign	0.016	T;T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.6	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.1	D;.;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.89
MVP		0.88
MPC		0.85
ClinPred		0.092	T
GERP RS		4.1
Varity_R		0.68
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs3729799; hg19: chr11-47355294; COSMIC: COSV99048609; COSMIC: COSV99048609;