rs3729952

chr11-47337495-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 4P and 20B. PM1 PM5 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000256.3(MYBPC3):c.2498C>T(p.Ala833Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,614,004 control chromosomes in the GnomAD database, including 29 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. A833T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0072 (12 hom., cov: 31)
  • Exomes 𝑓: 0.00073 (17 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 9.60

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 -16 ACMG points.

• PM1: In a domain Fibronectin type-III 1 (size 96) in uniprot entity MYPC3_HUMAN there are 50 pathogenic changes around while only 6 benign (89%) in NM_000256.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47337496-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.008352071).
• BP6: Variant 11-47337495-G-A is Benign according to our data. Variant chr11-47337495-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 42627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47337495-G-A is described in Lovd as [Likely_pathogenic]. Variant chr11-47337495-G-A is described in Lovd as [Likely_benign]. Variant chr11-47337495-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00719 (1095/152326) while in subpopulation AFR AF= 0.0245 (1020/41566). AF 95% confidence interval is 0.0233. There are 12 homozygotes in gnomad4. There are 543 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.2498C>T	p.Ala833Val	missense_variant	25/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2498C>T	p.Ala833Val	missense_variant	25/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.2498C>T	p.Ala833Val	missense_variant	24/34	5		A2
MYBPC3	ENST00000544791.1	c.*3C>T		3_prime_UTR_variant, NMD_transcript_variant	25/27	5

Frequencies

GnomAD3 genomes AF: 0.00720 AC: 1096 AN: 152208 Hom.: 13 Cov.: 31

Gnomad AFR AF: 0.0246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00196 AC: 488 AN: 249134 Hom.: 4 AF XY: 0.00151 AC XY: 204 AN XY: 135128

Gnomad AFR exome AF: 0.0282

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000732 AC: 1070 AN: 1461678 Hom.: 17 Cov.: 33 AF XY: 0.000634 AC XY: 461 AN XY: 727130

Gnomad4 AFR exome AF: 0.0261

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00719 AC: 1095 AN: 152326 Hom.: 12 Cov.: 31 AF XY: 0.00729 AC XY: 543 AN XY: 74486

Gnomad4 AFR AF: 0.0245

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00454 Hom.: 1

Bravo AF: 0.00818

ESP6500AA AF: 0.0224 AC: 97

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.00224 AC: 271

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 25, 2008	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 31006259, 24510615, 12974739, 21310275, 23299917, 22763267, 25342278, 12707239, 14563344) -

Left ventricular noncompaction 10 Benign:1

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. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 11, 2022

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 19, 2018

- -

Primary familial dilated cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jul 29, 2016

- -

Hypertrophic cardiomyopathy 4 Benign:1

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 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	0.19
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D
MetaRNN	Benign	0.0084	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.060	N;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.7	D;.;D
REVEL	Uncertain	0.30
Sift	Benign	0.24	T;.;T
Sift4G	Uncertain	0.036	D;D;D
Vest4		0.67
MVP		0.91
MPC		0.82
ClinPred		0.040	T
GERP RS		4.6
Varity_R		0.35
gMVP		0.54

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: rs3729952; hg19: chr11-47359046;