rs56259391

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002470.4(MYH3):c.2106C>T(p.Gly702Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0415 in 1,613,832 control chromosomes in the GnomAD database, including 1,896 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.058 ( 402 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1494 hom. )

Consequence

MYH3
NM_002470.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.879

Publications

6 publications found

Variant links:

Genes affected

MYH3 (HGNC:7573): (myosin heavy chain 3) Myosin is a major contractile protein which converts chemical energy into mechanical energy through the hydrolysis of ATP. Myosin is a hexameric protein composed of a pair of myosin heavy chains (MYH) and two pairs of nonidentical light chains. This gene is a member of the MYH family and encodes a protein with an IQ domain and a myosin head-like domain. Mutations in this gene have been associated with two congenital contracture (arthrogryposis) syndromes, Freeman-Sheldon syndrome and Sheldon-Hall syndrome. [provided by RefSeq, Jul 2008]

MYH3 links:

MYHAS (HGNC:50609): (myosin heavy chain gene cluster antisense RNA) Predicted to enable primary miRNA binding activity. Predicted to be involved in response to muscle activity and skeletal muscle fiber development. Predicted to act upstream of or within with a positive effect on gene expression. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

MYHAS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 17-10641144-G-A is Benign according to our data. Variant chr17-10641144-G-A is described in ClinVar as Benign. ClinVar VariationId is 129648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.879 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4 link	c.2106C>T	p.Gly702Gly	synonymous_variant	Exon 19 of 41	ENST00000583535.6	NP_002461.2	P11055Q5GJ67
MYH3	XM_011523870.4 link	c.2106C>T	p.Gly702Gly	synonymous_variant	Exon 19 of 41		XP_011522172.1	P11055
MYH3	XM_011523871.3 link	c.2106C>T	p.Gly702Gly	synonymous_variant	Exon 19 of 41		XP_011522173.1	P11055
MYH3	XM_047436127.1 link	c.2106C>T	p.Gly702Gly	synonymous_variant	Exon 21 of 43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYH3	ENST00000583535.6 link	c.2106C>T	p.Gly702Gly	synonymous_variant	Exon 19 of 41	5	NM_002470.4	ENSP00000464317.1	P11055
MYHAS	ENST00000579914.2 link	n.705+27267G>A		intron_variant	Intron 4 of 4	4
MYHAS	ENST00000584139.2 link	n.1041+27267G>A		intron_variant	Intron 7 of 8	3

Frequencies

GnomAD3 genomes

AF:

0.0583

AC:

8873

AN:

152126

Hom.:

402

Cov.:

show subpopulations

Gnomad AFR

AF:

0.127

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.0276

Gnomad ASJ

AF:

0.0291

Gnomad EAS

AF:

0.00885

Gnomad SAS

AF:

0.0700

Gnomad FIN

AF:

0.0137

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0354

Gnomad OTH

AF:

0.0430

GnomAD2 exomes

AF:

0.0388

AC:

9752

AN:

251444

AF XY:

0.0383

show subpopulations

Gnomad AFR exome

AF:

0.129

Gnomad AMR exome

AF:

0.0180

Gnomad ASJ exome

AF:

0.0240

Gnomad EAS exome

AF:

0.0105

Gnomad FIN exome

AF:

0.0161

Gnomad NFE exome

AF:

0.0352

Gnomad OTH exome

AF:

0.0354

GnomAD4 exome

AF:

0.0398

AC:

58099

AN:

1461588

Hom.:

1494

Cov.:

AF XY:

0.0397

AC XY:

28851

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.132

AC:

4424

AN:

33474

American (AMR)

AF:

0.0183

AC:

820

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0246

AC:

644

AN:

26136

East Asian (EAS)

AF:

0.00952

AC:

378

AN:

39700

South Asian (SAS)

AF:

0.0650

AC:

5604

AN:

86242

European-Finnish (FIN)

AF:

0.0171

AC:

915

AN:

53406

Middle Eastern (MID)

AF:

0.0381

AC:

213

AN:

5592

European-Non Finnish (NFE)

AF:

0.0382

AC:

42509

AN:

1111938

Other (OTH)

AF:

0.0429

AC:

2592

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

3347

6695

10042

13390

16737

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1698

3396

5094

6792

8490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0583

AC:

8876

AN:

152244

Hom.:

402

Cov.:

AF XY:

0.0563

AC XY:

4193

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.127

AC:

5265

AN:

41506

American (AMR)

AF:

0.0276

AC:

422

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0291

AC:

101

AN:

3472

East Asian (EAS)

AF:

0.00887

AC:

AN:

5186

South Asian (SAS)

AF:

0.0702

AC:

339

AN:

4826

European-Finnish (FIN)

AF:

0.0137

AC:

145

AN:

10612

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0354

AC:

2410

AN:

68026

Other (OTH)

AF:

0.0430

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

409

819

1228

1638

2047

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

106

212

318

424

530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0475

Hom.:

139

Bravo

AF:

0.0602

Asia WGS

AF:

0.0390

AC:

134

AN:

3478

EpiCase

AF:

0.0317

EpiControl

AF:

0.0331

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 26, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Freeman-Sheldon syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Distal arthrogryposis type 2B1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

-0.55

CADD

Benign

6.9

(source)

DANN

Benign

0.52

PhyloP100

-0.88

Mutation Taster

=79/21

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over