chr17-10649729-A-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.534-44T>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 1,580,702 control chromosomes in the GnomAD database, including 415,084 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.63 ( 32090 hom., cov: 32)

Exomes 𝑓: 0.72 ( 382994 hom. )

Consequence

MYH3
NM_002470.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.434

Publications

7 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

This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 5 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 17-10649729-A-G is Benign according to our data. Variant chr17-10649729-A-G is described in ClinVar as Benign. ClinVar VariationId is 258695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4 link	c.534-44T>C	intron_variant	Intron 6 of 40	ENST00000583535.6	NP_002461.2	P11055Q5GJ67
MYH3	XM_011523870.4 link	c.534-44T>C	intron_variant	Intron 6 of 40		XP_011522172.1	P11055
MYH3	XM_011523871.3 link	c.534-44T>C	intron_variant	Intron 6 of 40		XP_011522173.1	P11055
MYH3	XM_047436127.1 link	c.534-44T>C	intron_variant	Intron 8 of 42		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYH3	ENST00000583535.6 link	c.534-44T>C	intron_variant	Intron 6 of 40	5	NM_002470.4	ENSP00000464317.1	P11055
MYH3	ENST00000579489.2 link	n.486-44T>C	intron_variant	Intron 2 of 3	5
MYHAS	ENST00000579914.2 link	n.706-34206A>G	intron_variant	Intron 4 of 4	4
MYHAS	ENST00000584139.2 link	n.1042-31004A>G	intron_variant	Intron 7 of 8	3

Frequencies

GnomAD3 genomes

AF:

0.630

AC:

95764

AN:

151914

Hom.:

32081

Cov.:

show subpopulations

Gnomad AFR

AF:

0.420

Gnomad AMI

AF:

0.792

Gnomad AMR

AF:

0.588

Gnomad ASJ

AF:

0.732

Gnomad EAS

AF:

0.367

Gnomad SAS

AF:

0.592

Gnomad FIN

AF:

0.721

Gnomad MID

AF:

0.592

Gnomad NFE

AF:

0.769

Gnomad OTH

AF:

0.635

GnomAD2 exomes

AF:

0.648

AC:

162616

AN:

251048

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:

0.360

Gnomad FIN exome

AF:

0.731

Gnomad NFE exome

AF:

0.763

Gnomad OTH exome

AF:

0.687

GnomAD4 exome

AF:

0.725

AC:

1035758

AN:

1428670

Hom.:

382994

Cov.:

AF XY:

0.723

AC XY:

515946

AN XY:

713150

show subpopulations

African (AFR)

AF:

0.408

AC:

13309

AN:

32594

American (AMR)

AF:

0.497

AC:

22226

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.729

AC:

18873

AN:

25900

East Asian (EAS)

AF:

0.355

AC:

14010

AN:

39486

South Asian (SAS)

AF:

0.605

AC:

51755

AN:

85494

European-Finnish (FIN)

AF:

0.737

AC:

39275

AN:

53266

Middle Eastern (MID)

AF:

0.593

AC:

3378

AN:

5696

European-Non Finnish (NFE)

AF:

0.769

AC:

831758

AN:

1082288

Other (OTH)

AF:

0.695

AC:

41174

AN:

59270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

14822

29644

44465

59287

74109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19470

38940

58410

77880

97350

<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:

0.630

AC:

95798

AN:

152032

Hom.:

32090

Cov.:

AF XY:

0.623

AC XY:

46328

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.419

AC:

17367

AN:

41440

American (AMR)

AF:

0.589

AC:

8987

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.732

AC:

2537

AN:

3468

East Asian (EAS)

AF:

0.368

AC:

1897

AN:

5154

South Asian (SAS)

AF:

0.592

AC:

2856

AN:

4822

European-Finnish (FIN)

AF:

0.721

AC:

7630

AN:

10576

Middle Eastern (MID)

AF:

0.588

AC:

173

AN:

294

European-Non Finnish (NFE)

AF:

0.769

AC:

52284

AN:

67992

Other (OTH)

AF:

0.639

AC:

1345

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1662

3324

4986

6648

8310

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

774

1548

2322

3096

3870

<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:

0.708

Hom.:

16466

Bravo

AF:

0.606

Asia WGS

AF:

0.499

AC:

1739

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 12, 2018

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

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Freeman-Sheldon syndrome

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

- -

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

- -

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

6.0

(source)

DANN

Benign

0.26

PhyloP100

0.43

BranchPoint Hunter

5.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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