14-23420236-TG-TGG

Position:

• chr14-23420236-TG-TGG

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.3337-3dupC variant in the MYH7 gene is 0.23% (146/54400) 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/CA013590/MONDO:0004994/002

• Frequency:
  • Genomes: 𝑓 0.064 (363 hom., cov: 31)
  • Exomes 𝑓: 0.052 (3977 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH7 NM_000257.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:28
• Conservation: PhyloP100: 1.96

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.3337-3_3337-2insC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000355349.4
MYH7	NM_001407004.1	c.3337-3_3337-2insC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.3337-3_3337-2insC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000257.4	P1

Frequencies

GnomAD3 genomes AF: 0.0643 AC: 9763 AN: 151890 Hom.: 364 Cov.: 31

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.0733

Gnomad ASJ AF: 0.0875

Gnomad EAS AF: 0.0653

Gnomad SAS AF: 0.0949

Gnomad FIN AF: 0.0808

Gnomad MID AF: 0.0860

Gnomad NFE AF: 0.0754

Gnomad OTH AF: 0.0691

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0517 AC: 72348 AN: 1398654 Hom.: 3977 Cov.: 35 AF XY: 0.0522 AC XY: 36298 AN XY: 695764

Gnomad4 AFR exome AF: 0.0167

Gnomad4 AMR exome AF: 0.0279

Gnomad4 ASJ exome AF: 0.0654

Gnomad4 EAS exome AF: 0.0372

Gnomad4 SAS exome AF: 0.0724

Gnomad4 FIN exome AF: 0.0589

Gnomad4 NFE exome AF: 0.0519

Gnomad4 OTH exome AF: 0.0542

GnomAD4 genome AF: 0.0642 AC: 9755 AN: 152008 Hom.: 363 Cov.: 31 AF XY: 0.0645 AC XY: 4793 AN XY: 74288

Gnomad4 AFR AF: 0.0282

Gnomad4 AMR AF: 0.0732

Gnomad4 ASJ AF: 0.0875

Gnomad4 EAS AF: 0.0656

Gnomad4 SAS AF: 0.0947

Gnomad4 FIN AF: 0.0808

Gnomad4 NFE AF: 0.0754

Gnomad4 OTH AF: 0.0679

Alfa AF: 0.0555 Hom.: 63

Bravo AF: 0.0603

Asia WGS AF: 0.0720 AC: 251 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:28

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	May 12, 2017	BA1,BP6; This alteration has an allele frequency that is greater than 5% healthy populations (ExAC/gnomAD), and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 28, 2006	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 30, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 27, 2019	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 30, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	Allele frequency is common in at least one population database (frequency: 6.007% in gnomAD_Genomes) based on the frequency threshold of 0.637% for this gene. Variant was observed in a homozygous state in population databases more than expected for disease. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Cardiomyopathy Benign:3

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2018	- -
Benign, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The filtering allele frequency of the c.3337-3dupC variant in the MYH7 gene is 0.23% (146/54400) 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). -

Hypertrophic cardiomyopathy Benign:3

Benign, criteria provided, single submitter	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Cardiovascular phenotype Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 27, 2015	- -

Hypertrophic cardiomyopathy 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Dilated cardiomyopathy 1S Benign:1

Benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Ventricular fibrillation, paroxysmal familial, type 1 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Blueprint Genetics

Oct 17, 2013

- -

Myosin storage myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

MYH7-related skeletal myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated Cardiomyopathy, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Left ventricular noncompaction cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs45504498; hg19: chr14-23889445;