rs3729833

Variant names:

• chr14-23413975-C-T
• rs3729833
• NM_000257.4:c.5655+32G>A

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.5655+32G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,613,918 control chromosomes in the GnomAD database, including 21,580 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3257 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18323 hom.)
• Consequence: MYH7 NM_000257.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.39
• Publications: 10 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 14-23413975-C-T is Benign according to our data. Variant chr14-23413975-C-T is described in ClinVar as [Benign]. Clinvar id is 255632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.5655+32G>A		intron_variant	Intron 38 of 39	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.5655+32G>A		intron_variant	Intron 37 of 38		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.5655+32G>A		intron_variant	Intron 38 of 39	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.5655+32G>A		intron_variant	Intron 38 of 40			ENSP00000519070.1
MYH7	ENST00000713769.1	c.5655+32G>A		intron_variant	Intron 37 of 38			ENSP00000519071.1

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28201 AN: 152058 Hom.: 3249 Cov.: 32

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0420

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.180

GnomAD2 exomes AF: 0.125 AC: 31461 AN: 251330 AF XY: 0.120

Gnomad AFR exome AF: 0.321

Gnomad AMR exome AF: 0.0688

Gnomad ASJ exome AF: 0.173

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.150 AC: 218811 AN: 1461740 Hom.: 18323 Cov.: 34 AF XY: 0.146 AC XY: 106290 AN XY: 727178

African (AFR) AF: 0.318 AC: 10633 AN: 33470

American (AMR) AF: 0.0748 AC: 3346 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 4531 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0471 AC: 4061 AN: 86258

European-Finnish (FIN) AF: 0.111 AC: 5945 AN: 53352

Middle Eastern (MID) AF: 0.110 AC: 632 AN: 5768

European-Non Finnish (NFE) AF: 0.162 AC: 180552 AN: 1111944

Other (OTH) AF: 0.151 AC: 9107 AN: 60390

GnomAD4 genome AF: 0.186 AC: 28236 AN: 152178 Hom.: 3257 Cov.: 32 AF XY: 0.179 AC XY: 13291 AN XY: 74408

African (AFR) AF: 0.318 AC: 13208 AN: 41492

American (AMR) AF: 0.115 AC: 1766 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 598 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.0416 AC: 201 AN: 4828

European-Finnish (FIN) AF: 0.102 AC: 1076 AN: 10598

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.160 AC: 10890 AN: 67996

Other (OTH) AF: 0.178 AC: 377 AN: 2114

Alfa AF: 0.162 Hom.: 2951

Bravo AF: 0.191

Asia WGS AF: 0.0410 AC: 145 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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	7.9
DANN	Benign	0.57
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: rs3729833; hg19: chr14-23883184;