rs2285479

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.4731C>T(p.Ile1577Ile) 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 1,613,692 control chromosomes in the GnomAD database, including 379,821 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 27894 hom., cov: 32)

Exomes 𝑓: 0.69 ( 351927 hom. )

Consequence

MYH3
NM_002470.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -4.90

Publications

21 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:

LOC124903927 (HGNC:):

LOC124903927 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=-0.77).

BP6

Variant 17-10632701-G-A is Benign according to our data. Variant chr17-10632701-G-A is described in ClinVar as Benign. ClinVar VariationId is 129663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.9 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	UniProt
MYH3	NM_002470.4 link	c.4731C>T	p.Ile1577Ile	synonymous_variant	Exon 34 of 41	ENST00000583535.6	NP_002461.2	P11055Q5GJ67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYH3	ENST00000583535.6 link	c.4731C>T	p.Ile1577Ile	synonymous_variant	Exon 34 of 41	5	NM_002470.4	ENSP00000464317.1	P11055
MYHAS	ENST00000579914.2 link	n.705+18824G>A		intron_variant	Intron 4 of 4	4
MYHAS	ENST00000584139.2 link	n.1041+18824G>A		intron_variant	Intron 7 of 8	3
MYHAS	ENST00000781814.1 link	n.165-1984G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.575

AC:

87312

AN:

151846

Hom.:

27892

Cov.:

show subpopulations

Gnomad AFR

AF:

0.302

Gnomad AMI

AF:

0.746

Gnomad AMR

AF:

0.562

Gnomad ASJ

AF:

0.703

Gnomad EAS

AF:

0.370

Gnomad SAS

AF:

0.523

Gnomad FIN

AF:

0.707

Gnomad MID

AF:

0.548

Gnomad NFE

AF:

0.733

Gnomad OTH

AF:

0.591

GnomAD2 exomes

AF:

0.611

AC:

153517

AN:

251450

AF XY:

0.623

show subpopulations

Gnomad AFR exome

AF:

0.299

Gnomad AMR exome

AF:

0.467

Gnomad ASJ exome

AF:

0.708

Gnomad EAS exome

AF:

0.362

Gnomad FIN exome

AF:

0.714

Gnomad NFE exome

AF:

0.727

Gnomad OTH exome

AF:

0.652

GnomAD4 exome

AF:

0.686

AC:

1002231

AN:

1461728

Hom.:

351927

Cov.:

AF XY:

0.684

AC XY:

497622

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.282

AC:

9456

AN:

33480

American (AMR)

AF:

0.480

AC:

21468

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.705

AC:

18418

AN:

26136

East Asian (EAS)

AF:

0.367

AC:

14576

AN:

39698

South Asian (SAS)

AF:

0.540

AC:

46599

AN:

86254

European-Finnish (FIN)

AF:

0.720

AC:

38426

AN:

53404

Middle Eastern (MID)

AF:

0.559

AC:

3223

AN:

5768

European-Non Finnish (NFE)

AF:

0.729

AC:

810672

AN:

1111870

Other (OTH)

AF:

0.652

AC:

39393

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

18110

36220

54330

72440

90550

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:

0.575

AC:

87339

AN:

151964

Hom.:

27894

Cov.:

AF XY:

0.570

AC XY:

42322

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.301

AC:

12473

AN:

41406

American (AMR)

AF:

0.562

AC:

8585

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.703

AC:

2440

AN:

3470

East Asian (EAS)

AF:

0.371

AC:

1918

AN:

5166

South Asian (SAS)

AF:

0.523

AC:

2517

AN:

4812

European-Finnish (FIN)

AF:

0.707

AC:

7465

AN:

10560

Middle Eastern (MID)

AF:

0.545

AC:

159

AN:

292

European-Non Finnish (NFE)

AF:

0.733

AC:

49859

AN:

67976

Other (OTH)

AF:

0.591

AC:

1246

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1632

3264

4896

6528

8160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

728

1456

2184

2912

3640

<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:

0.674

Hom.:

55847

Bravo

AF:

0.549

Asia WGS

AF:

0.449

AC:

1567

AN:

3478

EpiCase

AF:

0.729

EpiControl

AF:

0.723

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

Clinical Genetics, Academic Medical Center

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

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

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

- -

Freeman-Sheldon syndrome

Benign:2

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. -

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

- -

Arthrogryposis, distal, type 2B3

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

-0.77

CADD

Benign

0.034

(source)

DANN

Benign

0.53

PhyloP100

-4.9

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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