rs11570076

chr11-47343571-G-Achr11-47343571-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000256.3(MYBPC3):c.1144C>T(p.Arg382Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00251 in 1,611,812 control chromosomes in the GnomAD database, including 105 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. R382G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (52 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (53 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 3.64

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 -18 ACMG points.

• PM1: In a domain Ig-like C2-type 2 (size 90) in uniprot entity MYPC3_HUMAN there are 25 pathogenic changes around while only 8 benign (76%) in NM_000256.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.010368973).
• BP6: Variant 11-47343571-G-A is Benign according to our data. Variant chr11-47343571-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 42506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47343571-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.013 (1974/151844) while in subpopulation AFR AF= 0.045 (1863/41388). AF 95% confidence interval is 0.0433. There are 52 homozygotes in gnomad4. There are 936 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 52 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.1144C>T	p.Arg382Trp	missense_variant	13/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1144C>T	p.Arg382Trp	missense_variant	13/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.1144C>T	p.Arg382Trp	missense_variant	12/34	5		A2
MYBPC3	ENST00000544791.1	c.1144C>T	p.Arg382Trp	missense_variant, NMD_transcript_variant	13/27	5

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1964 AN: 151726 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0449

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00466

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0130

GnomAD3 exomes AF: 0.00303 AC: 746 AN: 246538 Hom.: 16 AF XY: 0.00240 AC XY: 321 AN XY: 133986

Gnomad AFR exome AF: 0.0438

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000993

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000896

Gnomad OTH exome AF: 0.00267

GnomAD4 exome AF: 0.00142 AC: 2075 AN: 1459968 Hom.: 53 Cov.: 46 AF XY: 0.00119 AC XY: 862 AN XY: 726156

Gnomad4 AFR exome AF: 0.0495

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000233

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000828

Gnomad4 OTH exome AF: 0.00343

GnomAD4 genome AF: 0.0130 AC: 1974 AN: 151844 Hom.: 52 Cov.: 32 AF XY: 0.0126 AC XY: 936 AN XY: 74252

Gnomad4 AFR AF: 0.0450

Gnomad4 AMR AF: 0.00466

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00260 Hom.: 20

Bravo AF: 0.0146

ESP6500AA AF: 0.0314 AC: 126

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00368 AC: 445

Asia WGS AF: 0.00231 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 09, 2011	This variant is classified as benign based on its high frequency in the general population (rs11570076; MAF = 7%). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2011	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	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypertrophic cardiomyopathy Benign:3

Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Hypertrophic cardiomyopathy 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 19, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Left ventricular noncompaction 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 19, 2018

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 21, 2022

- -

Arrhythmogenic right ventricular dysplasia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Nov 15, 2019

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2015

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	0.34
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.32
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D;T;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.99	D;D;D
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Pathogenic	3.0	M;.;.
MutationTaster	Benign	0.74	N;N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0080	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.57
MVP		0.86
MPC		0.84
ClinPred		0.037	T
GERP RS		4.1
Varity_R		0.51
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11570076; hg19: chr11-47365122; COSMIC: COSV104563690;