rs201626

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.3348T>C(p.Ile1116Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,599,252 control chromosomes in the GnomAD database, including 20,966 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2539 hom., cov: 30)

Exomes 𝑓: 0.12 ( 18427 hom. )

Consequence

MYH3
NM_002470.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.54

Publications

13 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=-0.83).

BP6

Variant 17-10638424-A-G is Benign according to our data. Variant chr17-10638424-A-G is described in ClinVar as Benign. ClinVar VariationId is 129657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.54 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4 link	c.3348T>C	p.Ile1116Ile	synonymous_variant	Exon 27 of 41	ENST00000583535.6	NP_002461.2	P11055Q5GJ67
MYH3	XM_011523870.4 link	c.3348T>C	p.Ile1116Ile	synonymous_variant	Exon 27 of 41		XP_011522172.1	P11055
MYH3	XM_011523871.3 link	c.3348T>C	p.Ile1116Ile	synonymous_variant	Exon 27 of 41		XP_011522173.1	P11055
MYH3	XM_047436127.1 link	c.3348T>C	p.Ile1116Ile	synonymous_variant	Exon 29 of 43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYH3	ENST00000583535.6 link	c.3348T>C	p.Ile1116Ile	synonymous_variant	Exon 27 of 41	5	NM_002470.4	ENSP00000464317.1	P11055
MYHAS	ENST00000579914.2 link	n.705+24547A>G		intron_variant	Intron 4 of 4	4
MYHAS	ENST00000584139.2 link	n.1041+24547A>G		intron_variant	Intron 7 of 8	3

Frequencies

GnomAD3 genomes

AF:

0.150

AC:

22686

AN:

151524

Hom.:

2547

Cov.:

show subpopulations

Gnomad AFR

AF:

0.147

Gnomad AMI

AF:

0.0912

Gnomad AMR

AF:

0.251

Gnomad ASJ

AF:

0.184

Gnomad EAS

AF:

0.605

Gnomad SAS

AF:

0.245

Gnomad FIN

AF:

0.141

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.0874

Gnomad OTH

AF:

0.169

GnomAD2 exomes

AF:

0.199

AC:

47042

AN:

236198

AF XY:

0.190

show subpopulations

Gnomad AFR exome

AF:

0.144

Gnomad AMR exome

AF:

0.364

Gnomad ASJ exome

AF:

0.169

Gnomad EAS exome

AF:

0.614

Gnomad FIN exome

AF:

0.137

Gnomad NFE exome

AF:

0.0917

Gnomad OTH exome

AF:

0.171

GnomAD4 exome

AF:

0.122

AC:

176203

AN:

1447612

Hom.:

18427

Cov.:

AF XY:

0.124

AC XY:

89293

AN XY:

720532

show subpopulations

African (AFR)

AF:

0.152

AC:

5077

AN:

33472

American (AMR)

AF:

0.350

AC:

15649

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

4382

AN:

26136

East Asian (EAS)

AF:

0.602

AC:

23903

AN:

39682

South Asian (SAS)

AF:

0.231

AC:

19955

AN:

86224

European-Finnish (FIN)

AF:

0.131

AC:

5158

AN:

39500

Middle Eastern (MID)

AF:

0.161

AC:

927

AN:

5758

European-Non Finnish (NFE)

AF:

0.0829

AC:

92166

AN:

1111876

Other (OTH)

AF:

0.149

AC:

8986

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

8627

17253

25880

34506

43133

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3896

7792

11688

15584

19480

<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:

0.150

AC:

22694

AN:

151640

Hom.:

2539

Cov.:

AF XY:

0.159

AC XY:

11754

AN XY:

74054

show subpopulations

African (AFR)

AF:

0.147

AC:

6093

AN:

41348

American (AMR)

AF:

0.251

AC:

3816

AN:

15212

Ashkenazi Jewish (ASJ)

AF:

0.184

AC:

638

AN:

3466

East Asian (EAS)

AF:

0.604

AC:

3069

AN:

5080

South Asian (SAS)

AF:

0.246

AC:

1177

AN:

4790

European-Finnish (FIN)

AF:

0.141

AC:

1479

AN:

10512

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0875

AC:

5940

AN:

67924

Other (OTH)

AF:

0.167

AC:

351

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

890

1780

2671

3561

4451

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

240

480

720

960

1200

<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:

0.120

Hom.:

4382

Bravo

AF:

0.163

Asia WGS

AF:

0.373

AC:

1292

AN:

3478

EpiCase

AF:

0.0951

EpiControl

AF:

0.101

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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

- -

Oct 02, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

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

- -

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

-0.83

CADD

Benign

1.3

(source)

DANN

Benign

0.51

PhyloP100

-1.5

Mutation Taster

=97/3

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