rs147315081

chr11-47347669-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000256.3(MYBPC3):c.833G>A(p.Gly278Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000764 in 1,574,186 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (3 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 3.13

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068980753).
• BP6: Variant 11-47347669-C-T is Benign according to our data. Variant chr11-47347669-C-T is described in ClinVar as [Benign]. Clinvar id is 42797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47347669-C-T is described in Lovd as [Benign]. Variant chr11-47347669-C-T is described in Lovd as [Likely_pathogenic].
• BS2: High Homozygotes in GnomAd at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.833G>A	p.Gly278Glu	missense_variant	8/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.833G>A	p.Gly278Glu	missense_variant	8/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.833G>A	p.Gly278Glu	missense_variant	8/34	5		A2
MYBPC3	ENST00000544791.1	c.833G>A	p.Gly278Glu	missense_variant, NMD_transcript_variant	8/27	5

Frequencies

GnomAD3 genomes AF: 0.00388 AC: 590 AN: 152092 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

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: 0.00287

GnomAD3 exomes AF: 0.000971 AC: 181 AN: 186344 Hom.: 1 AF XY: 0.000690 AC XY: 69 AN XY: 100018

Gnomad AFR exome AF: 0.0147

Gnomad AMR exome AF: 0.000687

Gnomad ASJ exome AF: 0.000114

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000408

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000629

Gnomad OTH exome AF: 0.000415

GnomAD4 exome AF: 0.000429 AC: 610 AN: 1421976 Hom.: 3 Cov.: 33 AF XY: 0.000384 AC XY: 270 AN XY: 703630

Gnomad4 AFR exome AF: 0.0149

Gnomad4 AMR exome AF: 0.000880

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000916

Gnomad4 OTH exome AF: 0.00122

GnomAD4 genome AF: 0.00390 AC: 593 AN: 152210 Hom.: 6 Cov.: 32 AF XY: 0.00384 AC XY: 286 AN XY: 74418

Gnomad4 AFR AF: 0.0137

Gnomad4 AMR AF: 0.000981

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: 0.00284

Alfa AF: 0.000839 Hom.: 0

Bravo AF: 0.00449

ESP6500AA AF: 0.0157 AC: 62

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00116 AC: 138

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 17, 2020	p.Gly278Glu in exon 8 of MYBPC3: This variant is not expected to have clinical significance because it has been identified in 2.6% (76/2968) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs147315081). -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Aug 27, 2019	- -

Cardiomyopathy Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Feb 16, 2019	- -

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	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2018	This variant is associated with the following publications: (PMID: 12707239, 21310275, 26332594, 18403758, 20624503, 22763267, 23299917, 25525159, 27532831, 30871747) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 20, 2022	- -

Hypertrophic cardiomyopathy 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jun 07, 2016	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2017

This alteration is classified as benign based on a combination of the following: 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	-0.35	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.28	T;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	T;T;T
MetaRNN	Benign	0.0069	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	0.92	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.085	T;T;T
Sift4G	Benign	0.076	T;T;T
Polyphen		0.20	B;.;.
Vest4		0.59
MVP		0.81
MPC		0.56
ClinPred		0.075	T
GERP RS		3.3
Varity_R		0.11
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs147315081; hg19: chr11-47369220;