rs3729823

Variant names:

• chr14-23417200-G-C
• rs3729823
• NM_000257.4:c.4472C>G

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.4472C>G (p.Ser1491Cys) variant in the MYH7 gene is 0.98% (698/66740) 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA015008/MONDO:0004994/002

• Frequency:
  • Genomes: 𝑓 0.0085 (13 hom., cov: 33)
  • Exomes 𝑓: 0.012 (143 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Benign reviewed by expert panel B:27
• Conservation: PhyloP100: 7.79
• Publications: 24 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]

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.4472C>G	p.Ser1491Cys	missense	Exon 32 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.4472C>G	p.Ser1491Cys	missense	Exon 31 of 39	NP_001393933.1	P12883
	MHRT	NR_126491.1		n.652-12G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.4472C>G	p.Ser1491Cys	missense	Exon 32 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.4472C>G	p.Ser1491Cys	missense	Exon 32 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.4472C>G	p.Ser1491Cys	missense	Exon 32 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes AF: 0.00854 AC: 1299 AN: 152148 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00818 AC: 2058 AN: 251494 AF XY: 0.00836

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00639

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00231

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.00863

GnomAD4 exome AF: 0.0119 AC: 17342 AN: 1461892 Hom.: 143 Cov.: 34 AF XY: 0.0117 AC XY: 8506 AN XY: 727248

African (AFR) AF: 0.00215 AC: 72 AN: 33480

American (AMR) AF: 0.00704 AC: 315 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00195 AC: 51 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00715 AC: 617 AN: 86258

European-Finnish (FIN) AF: 0.00256 AC: 137 AN: 53420

Middle Eastern (MID) AF: 0.0107 AC: 62 AN: 5768

European-Non Finnish (NFE) AF: 0.0140 AC: 15525 AN: 1112010

Other (OTH) AF: 0.00929 AC: 561 AN: 60396

GnomAD4 genome AF: 0.00854 AC: 1300 AN: 152266 Hom.: 13 Cov.: 33 AF XY: 0.00786 AC XY: 585 AN XY: 74468

African (AFR) AF: 0.00250 AC: 104 AN: 41548

American (AMR) AF: 0.0123 AC: 189 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4822

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0135 AC: 920 AN: 68012

Other (OTH) AF: 0.0104 AC: 22 AN: 2110

Alfa AF: 0.0116 Hom.: 6

Bravo AF: 0.00928

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0156 AC: 60

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0115 AC: 99

ExAC AF: 0.00746 AC: 906

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0133

EpiControl AF: 0.0139

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	5	not provided (5)
-	-	4	Hypertrophic cardiomyopathy (4)
-	-	2	Hypertrophic cardiomyopathy 1 (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1S (1)
-	-	1	Hypertrophic cardiomyopathy;C0007196:Restrictive cardiomyopathy;C0878544:Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.40
Sift	Benign	0.035	D
Sift4G	Benign	0.16	T
Polyphen		0.0070	B
Vest4		0.56
MVP		0.94
MPC		0.89
ClinPred		0.044	T
GERP RS		5.3
Varity_R		0.34
gMVP		0.86
Mutation Taster		=17/83	disease causing

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: rs3729823; hg19: chr14-23886409;