rs3729818

Variant names:

• chr14-23425874-T-C
• rs3729818
• NM_000257.4:c.2163-56A>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.2163-56A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,610,288 control chromosomes in the GnomAD database, including 29,051 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6968 hom., cov: 32)
  • Exomes 𝑓: 0.16 (22083 hom.)
• Consequence: MYH7 NM_000257.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.36
• Publications: 3 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=-0.79).
• BP6: Variant 14-23425874-T-C is Benign according to our data. Variant chr14-23425874-T-C is described in ClinVar as Benign. ClinVar VariationId is 1265302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.2163-56A>G		intron_variant	Intron 19 of 39	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.2163-56A>G		intron_variant	Intron 18 of 38		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.2163-56A>G		intron_variant	Intron 19 of 39	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.2163-56A>G		intron_variant	Intron 19 of 40			ENSP00000519070.1
MYH7	ENST00000713769.1	c.2163-56A>G		intron_variant	Intron 18 of 38			ENSP00000519071.1

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38815 AN: 151990 Hom.: 6955 Cov.: 32

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.0808

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.235

GnomAD4 exome AF: 0.162 AC: 235501 AN: 1458180 Hom.: 22083 Cov.: 34 AF XY: 0.162 AC XY: 117196 AN XY: 725360

African (AFR) AF: 0.527 AC: 17579 AN: 33336

American (AMR) AF: 0.110 AC: 4921 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 5009 AN: 26092

East Asian (EAS) AF: 0.0561 AC: 2226 AN: 39674

South Asian (SAS) AF: 0.175 AC: 15076 AN: 86102

European-Finnish (FIN) AF: 0.139 AC: 7400 AN: 53370

Middle Eastern (MID) AF: 0.209 AC: 1037 AN: 4966

European-Non Finnish (NFE) AF: 0.155 AC: 171573 AN: 1109894

Other (OTH) AF: 0.177 AC: 10680 AN: 60172

GnomAD4 genome AF: 0.255 AC: 38859 AN: 152108 Hom.: 6968 Cov.: 32 AF XY: 0.248 AC XY: 18440 AN XY: 74350

African (AFR) AF: 0.518 AC: 21479 AN: 41440

American (AMR) AF: 0.163 AC: 2499 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 637 AN: 3468

East Asian (EAS) AF: 0.0810 AC: 420 AN: 5186

South Asian (SAS) AF: 0.175 AC: 840 AN: 4810

European-Finnish (FIN) AF: 0.136 AC: 1442 AN: 10604

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10714 AN: 67998

Other (OTH) AF: 0.232 AC: 491 AN: 2112

Alfa AF: 0.212 Hom.: 578

Bravo AF: 0.267

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.2
DANN	Benign	0.81
PhyloP100		-1.4
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: rs3729818; hg19: chr14-23895083; COSMIC: COSV62520021;