rs7159367

Variant names:

• chr14-23418436-T-C
• rs7159367
• NM_000257.4:c.3973-30A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000257.4(MYH7):​c.3973-30A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 1,582,748 control chromosomes in the GnomAD database, including 109,201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (15879 hom., cov: 33)
  • Exomes 𝑓: 0.35 (93322 hom.)
• Consequence: MYH7 NM_000257.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.547
• Publications: 6 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]

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 14-23418436-T-C is Benign according to our data. Variant chr14-23418436-T-C is described in ClinVar as Benign. ClinVar VariationId is 255630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.3973-30A>G		intron_variant	Intron 29 of 39	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.3973-30A>G		intron_variant	Intron 28 of 38		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.3973-30A>G		intron_variant	Intron 29 of 39	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.3973-30A>G		intron_variant	Intron 29 of 40			ENSP00000519070.1
MYH7	ENST00000713769.1	c.3973-30A>G		intron_variant	Intron 28 of 38			ENSP00000519071.1

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64316 AN: 151950 Hom.: 15843 Cov.: 33

Gnomad AFR AF: 0.683

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.0807

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.416

GnomAD2 exomes AF: 0.312 AC: 70251 AN: 225032 AF XY: 0.310

Gnomad AFR exome AF: 0.688

Gnomad AMR exome AF: 0.184

Gnomad ASJ exome AF: 0.412

Gnomad EAS exome AF: 0.0787

Gnomad FIN exome AF: 0.270

Gnomad NFE exome AF: 0.359

Gnomad OTH exome AF: 0.329

GnomAD4 exome AF: 0.350 AC: 500121 AN: 1430680 Hom.: 93322 Cov.: 36 AF XY: 0.346 AC XY: 244770 AN XY: 708410

African (AFR) AF: 0.692 AC: 22815 AN: 32954

American (AMR) AF: 0.200 AC: 8632 AN: 43256

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 10114 AN: 24610

East Asian (EAS) AF: 0.0555 AC: 2183 AN: 39334

South Asian (SAS) AF: 0.224 AC: 18501 AN: 82546

European-Finnish (FIN) AF: 0.273 AC: 12760 AN: 46754

Middle Eastern (MID) AF: 0.316 AC: 1691 AN: 5354

European-Non Finnish (NFE) AF: 0.367 AC: 402605 AN: 1096740

Other (OTH) AF: 0.352 AC: 20820 AN: 59132

GnomAD4 genome AF: 0.423 AC: 64390 AN: 152068 Hom.: 15879 Cov.: 33 AF XY: 0.410 AC XY: 30494 AN XY: 74326

African (AFR) AF: 0.683 AC: 28345 AN: 41490

American (AMR) AF: 0.289 AC: 4417 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1391 AN: 3466

East Asian (EAS) AF: 0.0809 AC: 417 AN: 5154

South Asian (SAS) AF: 0.214 AC: 1033 AN: 4816

European-Finnish (FIN) AF: 0.263 AC: 2784 AN: 10572

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.363 AC: 24672 AN: 67960

Other (OTH) AF: 0.411 AC: 866 AN: 2108

Alfa AF: 0.393 Hom.: 2369

Bravo AF: 0.435

Asia WGS AF: 0.179 AC: 625 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

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	-0.80
CADD	Benign	13
DANN	Benign	0.70
PhyloP100		-0.55
Mutation Taster		=100/0	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: rs7159367; hg19: chr14-23887645;