14-23420236-TG-TGG

Variant names:

• chr14-23420236-T-TG
• rs45504498
• NM_000257.4:c.3337-3dupC

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.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, intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:28
• Conservation: PhyloP100: 1.96
• Publications: 4 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: 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

ACMG classification

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.3337-3dupC		splice_region intron	N/A	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.3337-3dupC		splice_region intron	N/A	NP_001393933.1	P12883

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.3337-3_3337-2insC		splice_region intron	N/A	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.3337-3_3337-2insC		splice_region intron	N/A	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.3337-3_3337-2insC		splice_region intron	N/A	ENSP00000636014.1

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

GnomAD2 exomes AF: 0.0162 AC: 3863 AN: 238668 AF XY: 0.0153

Gnomad AFR exome AF: 0.00855

Gnomad AMR exome AF: 0.0166

Gnomad ASJ exome AF: 0.0137

Gnomad EAS exome AF: 0.0266

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.0146

Gnomad OTH exome AF: 0.0266

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0167 AC: 551 AN: 33076

American (AMR) AF: 0.0279 AC: 1226 AN: 43866

Ashkenazi Jewish (ASJ) AF: 0.0654 AC: 1635 AN: 24998

East Asian (EAS) AF: 0.0372 AC: 1460 AN: 39236

South Asian (SAS) AF: 0.0724 AC: 5980 AN: 82616

European-Finnish (FIN) AF: 0.0589 AC: 2992 AN: 50756

Middle Eastern (MID) AF: 0.0600 AC: 330 AN: 5504

European-Non Finnish (NFE) AF: 0.0519 AC: 55014 AN: 1060262

Other (OTH) AF: 0.0542 AC: 3160 AN: 58340

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.0282 AC: 1172 AN: 41498

American (AMR) AF: 0.0732 AC: 1117 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0875 AC: 303 AN: 3464

East Asian (EAS) AF: 0.0656 AC: 340 AN: 5182

South Asian (SAS) AF: 0.0947 AC: 454 AN: 4792

European-Finnish (FIN) AF: 0.0808 AC: 854 AN: 10564

Middle Eastern (MID) AF: 0.0753 AC: 22 AN: 292

European-Non Finnish (NFE) AF: 0.0754 AC: 5126 AN: 67950

Other (OTH) AF: 0.0679 AC: 143 AN: 2106

Alfa AF: 0.0555 Hom.: 63

Bravo AF: 0.0603

Asia WGS AF: 0.0720 AC: 251 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	1	3	not provided (4)
-	-	3	Cardiomyopathy (3)
-	-	3	Hypertrophic cardiomyopathy (3)
-	-	2	Cardiovascular phenotype (2)
-	-	2	Hypertrophic cardiomyopathy 1 (2)
-	-	1	Dilated cardiomyopathy 1S (1)
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Left ventricular noncompaction cardiomyopathy (1)
-	-	1	MYH7-related skeletal myopathy (1)
-	-	1	Myosin storage myopathy (1)
-	-	1	Ventricular fibrillation, paroxysmal familial, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=99/1	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: rs45504498; hg19: chr14-23889445; COSMIC: COSV62525047; COSMIC: COSV62525047;