rs2231124

chr14-23430584-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000257.4(MYH7):c.975C>T(p.Asp325=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0252 in 1,613,710 control chromosomes in the GnomAD database, including 592 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.019 (58 hom., cov: 32)
  • Exomes 𝑓: 0.026 (534 hom.)
• Consequence: MYH7 NM_000257.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:24
• Conservation: PhyloP100: -0.894

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=-0.6).
• BP6: Variant 14-23430584-G-A is Benign according to our data. Variant chr14-23430584-G-A is described in ClinVar as [Benign]. Clinvar id is 43116.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr14-23430584-G-A is described in Lovd as [Benign]. Variant chr14-23430584-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.894 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0186 (2831/152270) while in subpopulation NFE AF= 0.0262 (1781/68022). AF 95% confidence interval is 0.0252. There are 58 homozygotes in gnomad4. There are 1356 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 58 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.975C>T	p.Asp325=	synonymous_variant	11/40	ENST00000355349.4
MYH7	NM_001407004.1	c.975C>T	p.Asp325=	synonymous_variant	10/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.975C>T	p.Asp325=	synonymous_variant	11/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2828 AN: 152152 Hom.: 58 Cov.: 32

Gnomad AFR AF: 0.00468

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.0258

Gnomad ASJ AF: 0.0484

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00889

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0262

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.0205 AC: 5142 AN: 251162 Hom.: 62 AF XY: 0.0207 AC XY: 2815 AN XY: 135742

Gnomad AFR exome AF: 0.00449

Gnomad AMR exome AF: 0.0177

Gnomad ASJ exome AF: 0.0536

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00857

Gnomad FIN exome AF: 0.0140

Gnomad NFE exome AF: 0.0279

Gnomad OTH exome AF: 0.0290

GnomAD4 exome AF: 0.0259 AC: 37896 AN: 1461440 Hom.: 534 Cov.: 32 AF XY: 0.0254 AC XY: 18443 AN XY: 727032

Gnomad4 AFR exome AF: 0.00478

Gnomad4 AMR exome AF: 0.0194

Gnomad4 ASJ exome AF: 0.0515

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00944

Gnomad4 FIN exome AF: 0.0130

Gnomad4 NFE exome AF: 0.0289

Gnomad4 OTH exome AF: 0.0285

GnomAD4 genome AF: 0.0186 AC: 2831 AN: 152270 Hom.: 58 Cov.: 32 AF XY: 0.0182 AC XY: 1356 AN XY: 74472

Gnomad4 AFR AF: 0.00472

Gnomad4 AMR AF: 0.0257

Gnomad4 ASJ AF: 0.0484

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00931

Gnomad4 FIN AF: 0.0148

Gnomad4 NFE AF: 0.0262

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0257 Hom.: 28

Bravo AF: 0.0196

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:24

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:9

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Sep 20, 2019	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 18, 2008	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 18, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	May 22, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -

Cardiomyopathy Benign:2

Benign, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The filtering allele frequency of the c.975C>T (p.Asp325=) variant in the MYH7 gene is 2.82% (1920/65662) of European 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). -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2018	- -

Hypertrophic cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -

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. -

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. -

Dilated Cardiomyopathy, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Left ventricular noncompaction cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	6.0
Dann	Benign	0.36

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: rs2231124; hg19: chr14-23899793; COSMIC: COSV62522824;