chr17-10642813-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002470.4(MYH3):c.1581+13A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.716 in 1,613,388 control chromosomes in the GnomAD database, including 423,631 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.63 ( 32086 hom., cov: 31)

Exomes 𝑓: 0.72 ( 391545 hom. )

Consequence

MYH3
NM_002470.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.895

Publications

12 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 17-10642813-T-G is Benign according to our data. Variant chr17-10642813-T-G is described in ClinVar as Benign. ClinVar VariationId is 258671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.764 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4 link	c.1581+13A>C	intron_variant	Intron 15 of 40	ENST00000583535.6	NP_002461.2	P11055Q5GJ67
MYH3	XM_011523870.4 link	c.1581+13A>C	intron_variant	Intron 15 of 40		XP_011522172.1	P11055
MYH3	XM_011523871.3 link	c.1581+13A>C	intron_variant	Intron 15 of 40		XP_011522173.1	P11055
MYH3	XM_047436127.1 link	c.1581+13A>C	intron_variant	Intron 17 of 42		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYH3	ENST00000583535.6 link	c.1581+13A>C	intron_variant	Intron 15 of 40	5	NM_002470.4	ENSP00000464317.1	P11055
MYHAS	ENST00000579914.2 link	n.705+28936T>G	intron_variant	Intron 4 of 4	4
MYHAS	ENST00000584139.2 link	n.1041+28936T>G	intron_variant	Intron 7 of 8	3

Frequencies

GnomAD3 genomes

AF:

0.632

AC:

95718

AN:

151540

Hom.:

32078

Cov.:

show subpopulations

Gnomad AFR

AF:

0.421

Gnomad AMI

AF:

0.792

Gnomad AMR

AF:

0.590

Gnomad ASJ

AF:

0.731

Gnomad EAS

AF:

0.371

Gnomad SAS

AF:

0.592

Gnomad FIN

AF:

0.723

Gnomad MID

AF:

0.592

Gnomad NFE

AF:

0.769

Gnomad OTH

AF:

0.633

GnomAD2 exomes

AF:

0.648

AC:

162880

AN:

251420

AF XY:

0.660

show subpopulations

Gnomad AFR exome

AF:

0.419

Gnomad AMR exome

AF:

0.485

Gnomad ASJ exome

AF:

0.730

Gnomad EAS exome

AF:

0.361

Gnomad FIN exome

AF:

0.731

Gnomad NFE exome

AF:

0.763

Gnomad OTH exome

AF:

0.687

GnomAD4 exome

AF:

0.725

AC:

1059165

AN:

1461730

Hom.:

391545

Cov.:

120

AF XY:

0.723

AC XY:

525940

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.405

AC:

13566

AN:

33470

American (AMR)

AF:

0.498

AC:

22255

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.728

AC:

19032

AN:

26132

East Asian (EAS)

AF:

0.355

AC:

14074

AN:

39696

South Asian (SAS)

AF:

0.604

AC:

52111

AN:

86254

European-Finnish (FIN)

AF:

0.737

AC:

39384

AN:

53420

Middle Eastern (MID)

AF:

0.594

AC:

3428

AN:

5768

European-Non Finnish (NFE)

AF:

0.768

AC:

853419

AN:

1111904

Other (OTH)

AF:

0.694

AC:

41896

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

21192

42385

63577

84770

105962

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20196

40392

60588

80784

100980

<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:

0.631

AC:

95751

AN:

151658

Hom.:

32086

Cov.:

AF XY:

0.625

AC XY:

46292

AN XY:

74106

show subpopulations

African (AFR)

AF:

0.421

AC:

17333

AN:

41218

American (AMR)

AF:

0.590

AC:

8982

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.731

AC:

2539

AN:

3472

East Asian (EAS)

AF:

0.371

AC:

1897

AN:

5108

South Asian (SAS)

AF:

0.592

AC:

2843

AN:

4804

European-Finnish (FIN)

AF:

0.723

AC:

7641

AN:

10568

Middle Eastern (MID)

AF:

0.588

AC:

173

AN:

294

European-Non Finnish (NFE)

AF:

0.769

AC:

52284

AN:

67950

Other (OTH)

AF:

0.637

AC:

1337

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

1652

3303

4955

6606

8258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

772

1544

2316

3088

3860

<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:

0.706

Hom.:

100397

Bravo

AF:

0.606

Asia WGS

AF:

0.500

AC:

1742

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

- -

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 07, 2018

GeneDx

Significance: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

- -

Freeman-Sheldon syndrome

Benign:2

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. -

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 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

-0.90

CADD

Benign

0.12

(source)

DANN

Benign

0.34

PhyloP100

-0.90

Mutation Taster

=100/0

polymorphism (auto)

(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