rs3729833

Variant names:

Variant summary

Our verdict is The variant received -16 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_Strong

The NM_000257.4(MYH7):c.5655+32G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.153 (AC=247,047) in the gnomAD database across 1,613,918 control chromosomes, including 21,580 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.314. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3257 hom., cov: 32)

Exomes 𝑓: 0.15 ( 18323 hom. )

Consequence

MYH7
NM_000257.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.39

Publications

10 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 1S
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
myopathy, myosin storage, autosomal recessive
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
myopathy, myosin storage, autosomal dominant
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
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, G2P
congenital heart disease
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

MYH7 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000257.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

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

Classification was made for transcript

Our verdict: Benign. The variant received -16 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.3138 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	NM_000257.4	MANE Select	c.5655+32G>A		intron	N/A	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.5655+32G>A		intron	N/A	NP_001393933.1	P12883

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MYH7	ENST00000355349.4	TSL:1 MANE Select	c.5655+32G>A	intron	N/A	ENSP00000347507.3	P12883
MYH7	ENST00000858540.1		c.5700+32G>A	intron	N/A	ENSP00000528599.1	A0ACI8PLM0
MYH7	ENST00000965955.1		c.5700+32G>A	intron	N/A	ENSP00000636014.1	A0ACI8PLM0

Frequencies

GnomAD3 genomes

AF:

0.185

AC:

28201

AN:

152058

Hom.:

3249

Cov.:

show subpopulations

Gnomad AFR

AF:

0.318

Gnomad AMI

AF:

0.0899

Gnomad AMR

AF:

0.116

Gnomad ASJ

AF:

0.172

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0420

Gnomad FIN

AF:

0.102

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.160

Gnomad OTH

AF:

0.180

GnomAD2 exomes

AF:

0.125

AC:

31461

AN:

251330

AF XY:

0.120

show subpopulations

Gnomad AFR exome

AF:

0.321

Gnomad AMR exome

AF:

0.0688

Gnomad ASJ exome

AF:

0.173

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.105

Gnomad NFE exome

AF:

0.156

Gnomad OTH exome

AF:

0.134

GnomAD4 exome

AF:

0.150

AC:

218811

AN:

1461740

Hom.:

18323

Cov.:

AF XY:

0.146

AC XY:

106290

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.318

AC:

10633

AN:

33470

American (AMR)

AF:

0.0748

AC:

3346

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.173

AC:

4531

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0471

AC:

4061

AN:

86258

European-Finnish (FIN)

AF:

0.111

AC:

5945

AN:

53352

Middle Eastern (MID)

AF:

0.110

AC:

632

AN:

5768

European-Non Finnish (NFE)

AF:

0.162

AC:

180552

AN:

1111944

Other (OTH)

AF:

0.151

AC:

9107

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

11821

23643

35464

47286

59107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6384

12768

19152

25536

31920

<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:

0.186

AC:

28236

AN:

152178

Hom.:

3257

Cov.:

AF XY:

0.179

AC XY:

13291

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.318

AC:

13208

AN:

41492

American (AMR)

AF:

0.115

AC:

1766

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.172

AC:

598

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5174

South Asian (SAS)

AF:

0.0416

AC:

201

AN:

4828

European-Finnish (FIN)

AF:

0.102

AC:

1076

AN:

10598

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.160

AC:

10890

AN:

67996

Other (OTH)

AF:

0.178

AC:

377

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1126

2253

3379

4506

5632

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

278

556

834

1112

1390

<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:

0.162

Hom.:

2951

Bravo

AF:

0.191

Asia WGS

AF:

0.0410

AC:

145

AN:

3478

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.000171

AC:

AN:

122648

Turkish Variome

AF:

0.106

AC:

715

AN:

6714

Hom.:

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.000223

AC:

AN:

8960

Hom.:

ABraOM SABE-WGS-1171

AF:

0.179

AC:

419

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

7.9

(source)

DANN

Benign

0.57

PhyloP100

1.4

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over