rs735712

Variant names:

• chr14-23429851-G-A
• rs735712
• NM_000257.4:c.1062C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-23429851-G-A
• chr14-23429851-G-C
• chr14-23429851-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.1062C>T (p.Gly354=) variant in the MYH7 gene is 9.56% (1644/16510) of South Asian 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA010125/MONDO:0004994/002

• Frequency:
  • Genomes: 𝑓 0.063 (359 hom., cov: 32)
  • Exomes 𝑓: 0.074 (4188 hom.)
• Consequence: MYH7 NM_000257.4 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:20
• Conservation: PhyloP100: -8.29
• Publications: 17 publications found

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]

MYH7 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1S

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• MYH7-related skeletal myopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• myopathy, myosin storage, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• myopathy, myosin storage, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• congenital myopathy 7A, myosin storage, autosomal dominant

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ebstein anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyaline body myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000257.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	NM_000257.4	MANE Select	c.1062C>T	p.Gly354Gly	synonymous	Exon 12 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.1062C>T	p.Gly354Gly	synonymous	Exon 11 of 39	NP_001393933.1	P12883

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.1062C>T	p.Gly354Gly	synonymous	Exon 12 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.1062C>T	p.Gly354Gly	synonymous	Exon 12 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.1062C>T	p.Gly354Gly	synonymous	Exon 12 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes AF: 0.0632 AC: 9608 AN: 152020 Hom.: 360 Cov.: 32

Gnomad AFR AF: 0.0287

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.0741

Gnomad ASJ AF: 0.0925

Gnomad EAS AF: 0.0683

Gnomad SAS AF: 0.0978

Gnomad FIN AF: 0.0525

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0762

Gnomad OTH AF: 0.0699

GnomAD2 exomes AF: 0.0703 AC: 17686 AN: 251444 AF XY: 0.0740

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.0450

Gnomad ASJ exome AF: 0.0982

Gnomad EAS exome AF: 0.0677

Gnomad FIN exome AF: 0.0555

Gnomad NFE exome AF: 0.0769

Gnomad OTH exome AF: 0.0794

GnomAD4 exome AF: 0.0742 AC: 108412 AN: 1461748 Hom.: 4188 Cov.: 35 AF XY: 0.0754 AC XY: 54865 AN XY: 727186

African (AFR) AF: 0.0245 AC: 819 AN: 33476

American (AMR) AF: 0.0480 AC: 2145 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0976 AC: 2552 AN: 26136

East Asian (EAS) AF: 0.0539 AC: 2141 AN: 39698

South Asian (SAS) AF: 0.0986 AC: 8505 AN: 86254

European-Finnish (FIN) AF: 0.0588 AC: 3139 AN: 53372

Middle Eastern (MID) AF: 0.0868 AC: 498 AN: 5738

European-Non Finnish (NFE) AF: 0.0757 AC: 84205 AN: 1111964

Other (OTH) AF: 0.0730 AC: 4408 AN: 60386

GnomAD4 genome AF: 0.0631 AC: 9601 AN: 152138 Hom.: 359 Cov.: 32 AF XY: 0.0622 AC XY: 4625 AN XY: 74372

African (AFR) AF: 0.0286 AC: 1188 AN: 41518

American (AMR) AF: 0.0740 AC: 1131 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0925 AC: 321 AN: 3472

East Asian (EAS) AF: 0.0687 AC: 354 AN: 5156

South Asian (SAS) AF: 0.0978 AC: 471 AN: 4814

European-Finnish (FIN) AF: 0.0525 AC: 556 AN: 10592

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0762 AC: 5183 AN: 67980

Other (OTH) AF: 0.0687 AC: 145 AN: 2112

Alfa AF: 0.0667 Hom.: 234

Bravo AF: 0.0608

Asia WGS AF: 0.0760 AC: 264 AN: 3478

EpiCase AF: 0.0835

EpiControl AF: 0.0830

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	2	Cardiomyopathy (2)
-	-	2	Hypertrophic cardiomyopathy (2)
-	1	1	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Hypertrophic cardiomyopathy 1 (1)
-	-	1	Left ventricular noncompaction cardiomyopathy (1)
-	-	1	MYH7-related skeletal myopathy (1)
-	-	1	Myosin storage myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.3
DANN	Benign	0.71
PhyloP100		-8.3
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs735712; hg19: chr14-23899060;