rs2285474

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.2952T>C(p.Ser984Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 1,613,580 control chromosomes in the GnomAD database, including 379,800 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 27804 hom., cov: 32)

Exomes 𝑓: 0.69 ( 351996 hom. )

Consequence

MYH3
NM_002470.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -6.71

Publications

20 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=-0.98).

BP6

Variant 17-10639448-A-G is Benign according to our data. Variant chr17-10639448-A-G is described in ClinVar as Benign. ClinVar VariationId is 129653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-6.72 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MYH3	NM_002470.4 link	c.2952T>C	p.Ser984Ser	synonymous_variant	Exon 24 of 41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4 link	c.2952T>C	p.Ser984Ser	synonymous_variant	Exon 24 of 41		XP_011522172.1
MYH3	XM_011523871.3 link	c.2952T>C	p.Ser984Ser	synonymous_variant	Exon 24 of 41		XP_011522173.1
MYH3	XM_047436127.1 link	c.2952T>C	p.Ser984Ser	synonymous_variant	Exon 26 of 43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MYH3	ENST00000583535.6 link	c.2952T>C	p.Ser984Ser	synonymous_variant	Exon 24 of 41	5	NM_002470.4	ENSP00000464317.1
MYHAS	ENST00000579914.2 link	n.705+25571A>G		intron_variant	Intron 4 of 4	4
MYHAS	ENST00000584139.2 link	n.1041+25571A>G		intron_variant	Intron 7 of 8	3

Frequencies

GnomAD3 genomes

AF:

0.573

AC:

87028

AN:

151876

Hom.:

27798

Cov.:

show subpopulations

Gnomad AFR

AF:

0.295

Gnomad AMI

AF:

0.743

Gnomad AMR

AF:

0.561

Gnomad ASJ

AF:

0.703

Gnomad EAS

AF:

0.371

Gnomad SAS

AF:

0.523

Gnomad FIN

AF:

0.706

Gnomad MID

AF:

0.547

Gnomad NFE

AF:

0.734

Gnomad OTH

AF:

0.591

GnomAD2 exomes

AF:

0.610

AC:

153260

AN:

251126

AF XY:

0.622

show subpopulations

Gnomad AFR exome

AF:

0.294

Gnomad AMR exome

AF:

0.467

Gnomad ASJ exome

AF:

0.708

Gnomad EAS exome

AF:

0.362

Gnomad FIN exome

AF:

0.715

Gnomad NFE exome

AF:

0.728

Gnomad OTH exome

AF:

0.652

GnomAD4 exome

AF:

0.686

AC:

1002170

AN:

1461586

Hom.:

351996

Cov.:

AF XY:

0.684

AC XY:

497605

AN XY:

727094

show subpopulations

African (AFR)

AF:

0.277

AC:

9262

AN:

33474

American (AMR)

AF:

0.480

AC:

21452

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.705

AC:

18414

AN:

26136

East Asian (EAS)

AF:

0.368

AC:

14609

AN:

39698

South Asian (SAS)

AF:

0.540

AC:

46538

AN:

86248

European-Finnish (FIN)

AF:

0.720

AC:

38466

AN:

53418

Middle Eastern (MID)

AF:

0.556

AC:

3190

AN:

5736

European-Non Finnish (NFE)

AF:

0.729

AC:

810835

AN:

1111780

Other (OTH)

AF:

0.653

AC:

39404

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

18792

37583

56375

75166

93958

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19708

39416

59124

78832

98540

<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:

0.573

AC:

87060

AN:

151994

Hom.:

27804

Cov.:

AF XY:

0.568

AC XY:

42165

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.295

AC:

12223

AN:

41462

American (AMR)

AF:

0.561

AC:

8558

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.703

AC:

2441

AN:

3472

East Asian (EAS)

AF:

0.372

AC:

1927

AN:

5178

South Asian (SAS)

AF:

0.523

AC:

2512

AN:

4804

European-Finnish (FIN)

AF:

0.706

AC:

7430

AN:

10530

Middle Eastern (MID)

AF:

0.544

AC:

160

AN:

294

European-Non Finnish (NFE)

AF:

0.734

AC:

49876

AN:

67968

Other (OTH)

AF:

0.595

AC:

1258

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1623

3246

4870

6493

8116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

724

1448

2172

2896

3620

<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:

0.680

Hom.:

54936

Bravo

AF:

0.547

Asia WGS

AF:

0.464

AC:

1620

AN:

3478

EpiCase

AF:

0.730

EpiControl

AF:

0.724

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2019

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

- -

Freeman-Sheldon syndrome

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Arthrogryposis, distal, type 2B3

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Contractures, pterygia, and variable skeletal fusions syndrome 1B

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A

Benign:1

Sep 05, 2021

Genome-Nilou Lab

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

-0.98

CADD

Benign

0.0030

(source)

DANN

Benign

0.22

PhyloP100

-6.7

Mutation Taster

=96/4

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