chr17-10635411-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_002470.4(MYH3):c.4128C>T(p.Tyr1376Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00721 in 1,614,022 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 38 hom., cov: 33)

Exomes 𝑓: 0.0064 ( 79 hom. )

Consequence

MYH3
NM_002470.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.37

Publications

4 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=-0.8).

BP6

Variant 17-10635411-G-A is Benign according to our data. Variant chr17-10635411-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.37 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0151 (2293/152330) while in subpopulation AFR AF = 0.0399 (1660/41560). AF 95% confidence interval is 0.0383. There are 38 homozygotes in GnomAd4. There are 1076 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 38 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4 link	c.4128C>T	p.Tyr1376Tyr	synonymous_variant	Exon 30 of 41	ENST00000583535.6	NP_002461.2	P11055Q5GJ67
MYH3	XM_011523870.4 link	c.4128C>T	p.Tyr1376Tyr	synonymous_variant	Exon 30 of 41		XP_011522172.1	P11055
MYH3	XM_011523871.3 link	c.4128C>T	p.Tyr1376Tyr	synonymous_variant	Exon 30 of 41		XP_011522173.1	P11055
MYH3	XM_047436127.1 link	c.4128C>T	p.Tyr1376Tyr	synonymous_variant	Exon 32 of 43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYH3	ENST00000583535.6 link	c.4128C>T	p.Tyr1376Tyr	synonymous_variant	Exon 30 of 41	5	NM_002470.4	ENSP00000464317.1	P11055
MYHAS	ENST00000579914.2 link	n.705+21534G>A		intron_variant	Intron 4 of 4	4
MYHAS	ENST00000584139.2 link	n.1041+21534G>A		intron_variant	Intron 7 of 8	3
MYHAS	ENST00000781814.1 link	n.*88G>A		downstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2279

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0396

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00942

Gnomad ASJ

AF:

0.0138

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00849

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00531

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.00804

AC:

2021

AN:

251276

AF XY:

0.00794

show subpopulations

Gnomad AFR exome

AF:

0.0400

Gnomad AMR exome

AF:

0.00601

Gnomad ASJ exome

AF:

0.0171

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.00590

Gnomad OTH exome

AF:

0.00685

GnomAD4 exome

AF:

0.00639

AC:

9343

AN:

1461692

Hom.:

Cov.:

AF XY:

0.00640

AC XY:

4652

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.0419

AC:

1401

AN:

33472

American (AMR)

AF:

0.00651

AC:

291

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0178

AC:

466

AN:

26134

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.00879

AC:

758

AN:

86250

European-Finnish (FIN)

AF:

0.00129

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0206

AC:

119

AN:

5764

European-Non Finnish (NFE)

AF:

0.00512

AC:

5696

AN:

1111856

Other (OTH)

AF:

0.00893

AC:

539

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

632

1263

1895

2526

3158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

234

468

702

936

1170

<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:

0.0151

AC:

2293

AN:

152330

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1076

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0399

AC:

1660

AN:

41560

American (AMR)

AF:

0.00934

AC:

143

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0138

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00808

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000847

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00532

AC:

362

AN:

68032

Other (OTH)

AF:

0.0109

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

105

211

316

422

527

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.00963

Hom.:

Bravo

AF:

0.0169

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.00709

EpiControl

AF:

0.00658

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 24, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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. -

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

-0.80

CADD

Benign

1.1

(source)

DANN

Benign

0.88

PhyloP100

-1.4

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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