rs2285469

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.2532A>G(p.Ala844Ala) 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 1,613,870 control chromosomes in the GnomAD database, including 379,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 27823 hom., cov: 32)

Exomes 𝑓: 0.69 ( 352016 hom. )

Consequence

MYH3
NM_002470.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -11.4

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=-0.97).

BP6

Variant 17-10640146-T-C is Benign according to our data. Variant chr17-10640146-T-C is described in ClinVar as Benign. ClinVar VariationId is 129650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-11.4 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.2532A>G	p.Ala844Ala	synonymous_variant	Exon 22 of 41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4 link	c.2532A>G	p.Ala844Ala	synonymous_variant	Exon 22 of 41		XP_011522172.1
MYH3	XM_011523871.3 link	c.2532A>G	p.Ala844Ala	synonymous_variant	Exon 22 of 41		XP_011522173.1
MYH3	XM_047436127.1 link	c.2532A>G	p.Ala844Ala	synonymous_variant	Exon 24 of 43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MYH3	ENST00000583535.6 link	c.2532A>G	p.Ala844Ala	synonymous_variant	Exon 22 of 41	5	NM_002470.4	ENSP00000464317.1
MYHAS	ENST00000579914.2 link	n.705+26269T>C		intron_variant	Intron 4 of 4	4
MYHAS	ENST00000584139.2 link	n.1041+26269T>C		intron_variant	Intron 7 of 8	3

Frequencies

GnomAD3 genomes

AF:

0.573

AC:

87069

AN:

151896

Hom.:

27817

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:

0.707

Gnomad MID

AF:

0.547

Gnomad NFE

AF:

0.734

Gnomad OTH

AF:

0.591

GnomAD2 exomes

AF:

0.610

AC:

153466

AN:

251490

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:

1002301

AN:

1461856

Hom.:

352016

Cov.:

AF XY:

0.684

AC XY:

497675

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.277

AC:

9266

AN:

33480

American (AMR)

AF:

0.480

AC:

21453

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.705

AC:

18413

AN:

26134

East Asian (EAS)

AF:

0.368

AC:

14611

AN:

39700

South Asian (SAS)

AF:

0.539

AC:

46525

AN:

86258

European-Finnish (FIN)

AF:

0.720

AC:

38466

AN:

53420

Middle Eastern (MID)

AF:

0.557

AC:

3213

AN:

5766

European-Non Finnish (NFE)

AF:

0.729

AC:

810946

AN:

1111978

Other (OTH)

AF:

0.652

AC:

39408

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

21292

42584

63875

85167

106459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19714

39428

59142

78856

98570

<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:

87102

AN:

152014

Hom.:

27823

Cov.:

AF XY:

0.568

AC XY:

42214

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.295

AC:

12229

AN:

41462

American (AMR)

AF:

0.561

AC:

8577

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.703

AC:

2439

AN:

3468

East Asian (EAS)

AF:

0.372

AC:

1916

AN:

5156

South Asian (SAS)

AF:

0.523

AC:

2513

AN:

4808

European-Finnish (FIN)

AF:

0.707

AC:

7459

AN:

10548

Middle Eastern (MID)

AF:

0.544

AC:

160

AN:

294

European-Non Finnish (NFE)

AF:

0.734

AC:

49881

AN:

67982

Other (OTH)

AF:

0.595

AC:

1252

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1632

3264

4895

6527

8159

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:

0.664

Hom.:

26419

Bravo

AF:

0.547

Asia WGS

AF:

0.465

AC:

1623

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:6

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

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

- -

Aug 18, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Freeman-Sheldon syndrome

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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. -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

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 12, 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

-0.97

CADD

Benign

0.0020

(source)

DANN

Benign

0.32

PhyloP100

-11

Mutation Taster

=100/0

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