rs2231126

chr14-23429785-G-Achr14-23429785-G-Cchr14-23429785-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000257.4(MYH7):c.1128C>T(p.Asp376=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0914 in 1,612,304 control chromosomes in the GnomAD database, including 10,510 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.16 (3364 hom., cov: 31)
  • Exomes 𝑓: 0.084 (7146 hom.)
• Consequence: MYH7 NM_000257.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:20
• Conservation: PhyloP100: -0.614

Genes affected

MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 14-23429785-G-A is Benign according to our data. Variant chr14-23429785-G-A is described in ClinVar as [Benign]. Clinvar id is 42823.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr14-23429785-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.614 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.1128C>T	p.Asp376=	synonymous_variant	12/40	ENST00000355349.4
MYH7	NM_001407004.1	c.1128C>T	p.Asp376=	synonymous_variant	11/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.1128C>T	p.Asp376=	synonymous_variant	12/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24254 AN: 151840 Hom.: 3357 Cov.: 31

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.0527

Gnomad AMR AF: 0.0799

Gnomad ASJ AF: 0.0914

Gnomad EAS AF: 0.0151

Gnomad SAS AF: 0.0736

Gnomad FIN AF: 0.0542

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0809

Gnomad OTH AF: 0.145

GnomAD3 exomes AF: 0.0893 AC: 22438 AN: 251366 Hom.: 1865 AF XY: 0.0855 AC XY: 11615 AN XY: 135862

Gnomad AFR exome AF: 0.387

Gnomad AMR exome AF: 0.0534

Gnomad ASJ exome AF: 0.0927

Gnomad EAS exome AF: 0.0135

Gnomad SAS exome AF: 0.0742

Gnomad FIN exome AF: 0.0526

Gnomad NFE exome AF: 0.0808

Gnomad OTH exome AF: 0.0865

GnomAD4 exome AF: 0.0843 AC: 123116 AN: 1460346 Hom.: 7146 Cov.: 34 AF XY: 0.0834 AC XY: 60624 AN XY: 726492

Gnomad4 AFR exome AF: 0.393

Gnomad4 AMR exome AF: 0.0572

Gnomad4 ASJ exome AF: 0.0945

Gnomad4 EAS exome AF: 0.00960

Gnomad4 SAS exome AF: 0.0743

Gnomad4 FIN exome AF: 0.0542

Gnomad4 NFE exome AF: 0.0799

Gnomad4 OTH exome AF: 0.0974

GnomAD4 genome AF: 0.160 AC: 24292 AN: 151958 Hom.: 3364 Cov.: 31 AF XY: 0.153 AC XY: 11345 AN XY: 74254

Gnomad4 AFR AF: 0.383

Gnomad4 AMR AF: 0.0797

Gnomad4 ASJ AF: 0.0914

Gnomad4 EAS AF: 0.0149

Gnomad4 SAS AF: 0.0736

Gnomad4 FIN AF: 0.0542

Gnomad4 NFE AF: 0.0809

Gnomad4 OTH AF: 0.144

Alfa AF: 0.0979 Hom.: 895

Bravo AF: 0.172

Asia WGS AF: 0.0730 AC: 254 AN: 3478

EpiCase AF: 0.0903

EpiControl AF: 0.0875

ClinVar

Significance: Benign

Submissions summary: Benign:20

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:9

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jan 17, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 18, 2008	- -

Cardiomyopathy Benign:3

Benign, criteria provided, single submitter	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2018	- -
Benign, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The filtering allele frequency of the c.1128C>T (p.Asp376=) variant in the MYH7 gene is 37.6% (4016/10404) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). -

Dilated cardiomyopathy 1S 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. -

MYH7-related skeletal myopathy 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. -

Myosin storage myopathy 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Left ventricular noncompaction cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 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. -

Hypertrophic cardiomyopathy 1 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	0.17
Dann	Benign	0.64

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: rs2231126; hg19: chr14-23898994; COSMIC: COSV62521087;