rs3729989

Positions:

• chr11-47348490-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000256.3(MYBPC3):​c.706A>G​(p.Ser236Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,612,892 control chromosomes in the GnomAD database, including 12,149 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (786 hom., cov: 30)
  • Exomes 𝑓: 0.12 (11363 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 3.19

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 1 (size 103) in uniprot entity MYPC3_HUMAN there are 30 pathogenic changes around while only 10 benign (75%) in NM_000256.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0027847886).
• BP6: Variant 11-47348490-T-C is Benign according to our data. Variant chr11-47348490-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 42786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47348490-T-C is described in Lovd as [Benign]. Variant chr11-47348490-T-C is described in Lovd as [Likely_pathogenic]. Variant chr11-47348490-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.706A>G	p.Ser236Gly	missense_variant	6/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.706A>G	p.Ser236Gly	missense_variant	6/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.706A>G	p.Ser236Gly	missense_variant	6/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.706A>G	p.Ser236Gly	missense_variant, NMD_transcript_variant	6/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes AF: 0.0947 AC: 14397 AN: 152056 Hom.: 784 Cov.: 30

Gnomad AFR AF: 0.0535

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0746

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0276

Gnomad SAS AF: 0.0617

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.0889

GnomAD3 exomes AF: 0.0964 AC: 23868 AN: 247526 Hom.: 1373 AF XY: 0.0978 AC XY: 13161 AN XY: 134536

Gnomad AFR exome AF: 0.0536

Gnomad AMR exome AF: 0.0459

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.0291

Gnomad SAS exome AF: 0.0682

Gnomad FIN exome AF: 0.119

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.120 AC: 175560 AN: 1460718 Hom.: 11363 Cov.: 32 AF XY: 0.119 AC XY: 86305 AN XY: 726614

Gnomad4 AFR exome AF: 0.0521

Gnomad4 AMR exome AF: 0.0487

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.0181

Gnomad4 SAS exome AF: 0.0704

Gnomad4 FIN exome AF: 0.127

Gnomad4 NFE exome AF: 0.133

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome AF: 0.0947 AC: 14417 AN: 152174 Hom.: 786 Cov.: 30 AF XY: 0.0923 AC XY: 6869 AN XY: 74402

Gnomad4 AFR AF: 0.0539

Gnomad4 AMR AF: 0.0744

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.0276

Gnomad4 SAS AF: 0.0622

Gnomad4 FIN AF: 0.121

Gnomad4 NFE AF: 0.128

Gnomad4 OTH AF: 0.0880

Alfa AF: 0.117 Hom.: 2877

Bravo AF: 0.0894

TwinsUK AF: 0.135 AC: 501

ALSPAC AF: 0.135 AC: 519

ESP6500AA AF: 0.0574 AC: 239

ESP6500EA AF: 0.126 AC: 1060

ExAC AF: 0.100 AC: 12114

Asia WGS AF: 0.0500 AC: 174 AN: 3478

EpiCase AF: 0.125

EpiControl AF: 0.129

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:23

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	Jan 18, 2008	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hypertrophic cardiomyopathy 4 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Benign, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -

Hypertrophic cardiomyopathy Benign:4

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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	- -

Left ventricular noncompaction 10 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 19, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 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	Benign	0.14
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.22
DEOGEN2	Benign	0.15	T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.56	T;T;T
MetaRNN	Benign	0.0028	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.7	N;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.39	T
PROVEAN	Benign	2.2	N;N;N
REVEL	Benign	0.17
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.031
MPC		0.20
ClinPred		0.0085	T
GERP RS		5.1
Varity_R		0.15
gMVP		0.44

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

Other links and lift over

dbSNP: rs3729989; hg19: chr11-47370041;