rs114978322

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000257.4(MYH7):c.3972+16G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000859 in 1,612,656 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00053 ( 6 hom. )

Consequence

MYH7
NM_000257.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -3.23

Publications

2 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
hypertrophic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hypertrophic cardiomyopathy 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
MYH7-related skeletal myopathy
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 14-23419161-C-T is Benign according to our data. Variant chr14-23419161-C-T is described in ClinVar as [Benign]. Clinvar id is 188631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00397 (605/152334) while in subpopulation AFR AF = 0.0133 (553/41568). AF 95% confidence interval is 0.0124. There are 3 homozygotes in GnomAd4. There are 283 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4 link	c.3972+16G>A		intron_variant	Intron 29 of 39	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 link	c.3972+16G>A		intron_variant	Intron 28 of 38		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYH7	ENST00000355349.4 link	c.3972+16G>A	intron_variant	Intron 29 of 39	1	NM_000257.4	ENSP00000347507.3	P12883
MYH7	ENST00000713768.1 link	c.3972+16G>A	intron_variant	Intron 29 of 40			ENSP00000519070.1
MYH7	ENST00000713769.1 link	c.3972+16G>A	intron_variant	Intron 28 of 38			ENSP00000519071.1

Frequencies

GnomAD3 genomes

AF:

0.00397

AC:

605

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00113

AC:

283

AN:

251444

AF XY:

0.000773

show subpopulations

Gnomad AFR exome

AF:

0.0149

Gnomad AMR exome

AF:

0.000491

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000535

AC:

781

AN:

1460322

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

322

AN XY:

726592

show subpopulations

African (AFR)

AF:

0.0167

AC:

560

AN:

33440

American (AMR)

AF:

0.000760

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.000116

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000585

AC:

AN:

1110620

Other (OTH)

AF:

0.00141

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

128

170

213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00397

AC:

605

AN:

152334

Hom.:

Cov.:

AF XY:

0.00380

AC XY:

283

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0133

AC:

553

AN:

41568

American (AMR)

AF:

0.00235

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000829

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68032

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

100

134

167

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00322

Hom.:

Bravo

AF:

0.00504

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 11, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MYH7 c.3972+16G>A alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0011 in 251444 control chromosomes, predominantly at a frequency of 0.015 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 11.99 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH7 causing Cardiomyopathy phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.3972+16G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:1

Jul 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.035

(source)

DANN

Benign

0.35

PhyloP100

-3.2

Mutation Taster

=100/0

polymorphism

(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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rs114978322

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over