14-23415680-C-T

Variant names:

• chr14-23415680-C-T
• rs3729830
• NM_000257.4:c.5106G>A

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.5106G>A (p.Ala1702=) variant in the MYH7 gene is 22.43% (2414/10406) 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA015682/MONDO:0004994/002

• Frequency:
  • Genomes: 𝑓 0.14 (1834 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11618 hom.)
• Consequence: MYH7 NM_000257.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:22
• Conservation: PhyloP100: -7.43
• Publications: 10 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]

ENSG00000258444 (HGNC:):

MHRT (HGNC:51291): (myosin heavy chain associated RNA transcript) This gene encodes a spliced long non-coding RNA that may act as a cardioprotective agent in the heart. Based on a study of a similar gene in mouse, the encoded transcript may regulate chromatin remodeling by acting as a decoy to the BRG1 chromatin repressor complex thus preventing it from binding to its genomic targets. Blocking the actions of BRG1 could be crucial in protecting the heart from pathological hypertrophy. [provided by RefSeq, Dec 2014]

ACMG classification

Specifications for MYH7 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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.5106G>A	p.Ala1702Ala	synonymous	Exon 35 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.5106G>A	p.Ala1702Ala	synonymous	Exon 34 of 39	NP_001393933.1	P12883
	MHRT	NR_126491.1		n.112C>T		non_coding_transcript_exon	Exon 2 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.5106G>A	p.Ala1702Ala	synonymous	Exon 35 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.5106G>A	p.Ala1702Ala	synonymous	Exon 35 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.5106G>A	p.Ala1702Ala	synonymous	Exon 35 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21546 AN: 152108 Hom.: 1830 Cov.: 32

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.0898

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.0152

Gnomad SAS AF: 0.0782

Gnomad FIN AF: 0.0781

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.138

GnomAD2 exomes AF: 0.104 AC: 26178 AN: 251102 AF XY: 0.105

Gnomad AFR exome AF: 0.227

Gnomad AMR exome AF: 0.0645

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.0141

Gnomad FIN exome AF: 0.0731

Gnomad NFE exome AF: 0.123

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.122 AC: 177608 AN: 1461738 Hom.: 11618 Cov.: 35 AF XY: 0.120 AC XY: 87423 AN XY: 727164

African (AFR) AF: 0.234 AC: 7837 AN: 33476

American (AMR) AF: 0.0702 AC: 3138 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 3444 AN: 26136

East Asian (EAS) AF: 0.0101 AC: 401 AN: 39700

South Asian (SAS) AF: 0.0810 AC: 6991 AN: 86258

European-Finnish (FIN) AF: 0.0751 AC: 4005 AN: 53318

Middle Eastern (MID) AF: 0.114 AC: 655 AN: 5736

European-Non Finnish (NFE) AF: 0.129 AC: 143905 AN: 1112000

Other (OTH) AF: 0.120 AC: 7232 AN: 60390

GnomAD4 genome AF: 0.142 AC: 21564 AN: 152226 Hom.: 1834 Cov.: 32 AF XY: 0.136 AC XY: 10140 AN XY: 74426

African (AFR) AF: 0.228 AC: 9474 AN: 41510

American (AMR) AF: 0.0895 AC: 1370 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 427 AN: 3472

East Asian (EAS) AF: 0.0151 AC: 78 AN: 5182

South Asian (SAS) AF: 0.0780 AC: 376 AN: 4820

European-Finnish (FIN) AF: 0.0781 AC: 829 AN: 10610

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.127 AC: 8620 AN: 68008

Other (OTH) AF: 0.137 AC: 289 AN: 2114

Alfa AF: 0.137 Hom.: 825

Bravo AF: 0.149

Asia WGS AF: 0.0640 AC: 222 AN: 3478

EpiCase AF: 0.131

EpiControl AF: 0.130

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	3	Cardiomyopathy (3)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy (1)
-	-	1	Dilated cardiomyopathy 1S (1)
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 1 (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	-0.86
CADD	Benign	0.040
DANN	Benign	0.85
PhyloP100		-7.4
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3729830; hg19: chr14-23884889; COSMIC: COSV108170768; COSMIC: COSV108170768;