NM_000257.4:c.3853+7C>T

Variant names:

• chr14-23419476-G-A
• rs45467397
• NM_000257.4:c.3853+7C>T

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.3853+7C>T variant in the MYH7 gene is 0.32% (239/66734) 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/CA014162/MONDO:0004994/002

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0037 (15 hom.)
• Consequence: MYH7 NM_000257.4 splice_region, intron
• Scores: Splicing: ADA: 0.00005757
• Clinical Significance: Benign reviewed by expert panel U:1 B:19
• Conservation: PhyloP100: 0.469
• 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.3853+7C>T		splice_region intron	N/A	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.3853+7C>T		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.3853+7C>T		splice_region intron	N/A	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.3853+7C>T		splice_region intron	N/A	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.3853+7C>T		splice_region intron	N/A	ENSP00000636014.1

Frequencies

GnomAD3 genomes AF: 0.00236 AC: 359 AN: 152158 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00428

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00230 AC: 579 AN: 251378 AF XY: 0.00229

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000510

Gnomad NFE exome AF: 0.00409

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00367 AC: 5363 AN: 1461664 Hom.: 15 Cov.: 45 AF XY: 0.00361 AC XY: 2625 AN XY: 727168

African (AFR) AF: 0.000807 AC: 27 AN: 33472

American (AMR) AF: 0.00154 AC: 69 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00111 AC: 59 AN: 53316

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5710

European-Non Finnish (NFE) AF: 0.00452 AC: 5024 AN: 1111978

Other (OTH) AF: 0.00293 AC: 177 AN: 60378

GnomAD4 genome AF: 0.00236 AC: 359 AN: 152276 Hom.: 1 Cov.: 31 AF XY: 0.00215 AC XY: 160 AN XY: 74460

African (AFR) AF: 0.000746 AC: 31 AN: 41550

American (AMR) AF: 0.00163 AC: 25 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00428 AC: 291 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00315 Hom.: 0

Bravo AF: 0.00246

EpiCase AF: 0.00322

EpiControl AF: 0.00439

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	not provided (4)
-	-	2	Cardiomyopathy (2)
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	1	-	Hypertrophic cardiomyopathy 1 (1)
-	-	1	Left ventricular noncompaction cardiomyopathy (1)
-	-	1	MYH7-related skeletal myopathy (1)
-	-	1	Myosin storage myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.8
DANN	Benign	0.88
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000058
dbscSNV1_RF	Benign	0.0020
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: rs45467397; hg19: chr14-23888685; COSMIC: COSV108170874;