14-23429785-G-A

Variant names:

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.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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA010240/MONDO:0004994/002

Frequency

Genomes: 𝑓 0.16 ( 3364 hom., cov: 31)

Exomes 𝑓: 0.084 ( 7146 hom. )

Consequence

MYH7
NM_000257.4 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:21

Conservation

PhyloP100: -0.614

Publications

12 publications found

Variant links:

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

MYH7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.1128C>T	p.Asp376Asp	synonymous	Exon 12 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.1128C>T	p.Asp376Asp	synonymous	Exon 11 of 39	NP_001393933.1	P12883

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYH7	ENST00000355349.4	TSL:1 MANE Select	c.1128C>T	p.Asp376Asp	synonymous	Exon 12 of 40	ENSP00000347507.3	P12883
MYH7	ENST00000858540.1		c.1128C>T	p.Asp376Asp	synonymous	Exon 12 of 40	ENSP00000528599.1
MYH7	ENST00000965955.1		c.1128C>T	p.Asp376Asp	synonymous	Exon 12 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes

AF:

0.160

AC:

24254

AN:

151840

Hom.:

3357

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0893

AC:

22438

AN:

251366

AF XY:

0.0855

show subpopulations

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 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.:

AF XY:

0.0834

AC XY:

60624

AN XY:

726492

show subpopulations

African (AFR)

AF:

0.393

AC:

13140

AN:

33436

American (AMR)

AF:

0.0572

AC:

2559

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0945

AC:

2471

AN:

26136

East Asian (EAS)

AF:

0.00960

AC:

381

AN:

39696

South Asian (SAS)

AF:

0.0743

AC:

6405

AN:

86188

European-Finnish (FIN)

AF:

0.0542

AC:

2888

AN:

53270

Middle Eastern (MID)

AF:

0.114

AC:

533

AN:

4684

European-Non Finnish (NFE)

AF:

0.0799

AC:

88870

AN:

1111944

Other (OTH)

AF:

0.0974

AC:

5869

AN:

60272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

6526

13052

19578

26104

32630

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3376

6752

10128

13504

16880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.160

AC:

24292

AN:

151958

Hom.:

3364

Cov.:

AF XY:

0.153

AC XY:

11345

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.383

AC:

15876

AN:

41418

American (AMR)

AF:

0.0797

AC:

1217

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0914

AC:

317

AN:

3470

East Asian (EAS)

AF:

0.0149

AC:

AN:

5166

South Asian (SAS)

AF:

0.0736

AC:

354

AN:

4808

European-Finnish (FIN)

AF:

0.0542

AC:

571

AN:

10544

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0809

AC:

5495

AN:

67964

Other (OTH)

AF:

0.144

AC:

304

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

892

1784

2675

3567

4459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

232

464

696

928

1160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.101

Hom.:

1042

Bravo

AF:

0.172

Asia WGS

AF:

0.0730

AC:

254

AN:

3478

EpiCase

AF:

0.0903

EpiControl

AF:

0.0875

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (9)

Cardiomyopathy (3)

not provided (2)

Cardiovascular phenotype (1)

Dilated cardiomyopathy 1S (1)

Hypertrophic cardiomyopathy (1)

Hypertrophic cardiomyopathy 1 (1)

Left ventricular noncompaction cardiomyopathy (1)

MYH7-related skeletal myopathy (1)

Myosin storage myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.17

(source)

DANN

Benign

0.64

PhyloP100

-0.61

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over