17-10641099-G-T

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.2151C>A(p.Gly717Gly) 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 1,604,760 control chromosomes in the GnomAD database, including 377,892 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G717G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.57 ( 27839 hom., cov: 32)

Exomes 𝑓: 0.69 ( 350053 hom. )

Consequence

MYH3
NM_002470.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.23

Publications

19 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=-0.72).

BP6

Variant 17-10641099-G-T is Benign according to our data. Variant chr17-10641099-G-T is described in ClinVar as [Benign]. Clinvar id is 129649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.23 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.729 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4 link	c.2151C>A	p.Gly717Gly	synonymous_variant	Exon 19 of 41	ENST00000583535.6	NP_002461.2	P11055Q5GJ67
MYH3	XM_011523870.4 link	c.2151C>A	p.Gly717Gly	synonymous_variant	Exon 19 of 41		XP_011522172.1	P11055
MYH3	XM_011523871.3 link	c.2151C>A	p.Gly717Gly	synonymous_variant	Exon 19 of 41		XP_011522173.1	P11055
MYH3	XM_047436127.1 link	c.2151C>A	p.Gly717Gly	synonymous_variant	Exon 21 of 43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYH3	ENST00000583535.6 link	c.2151C>A	p.Gly717Gly	synonymous_variant	Exon 19 of 41	5	NM_002470.4	ENSP00000464317.1	P11055
MYHAS	ENST00000579914.2 link	n.705+27222G>T		intron_variant	Intron 4 of 4	4
MYHAS	ENST00000584139.2 link	n.1041+27222G>T		intron_variant	Intron 7 of 8	3

Frequencies

GnomAD3 genomes

AF:

0.574

AC:

87116

AN:

151862

Hom.:

27832

Cov.:

show subpopulations

Gnomad AFR

AF:

0.296

Gnomad AMI

AF:

0.743

Gnomad AMR

AF:

0.562

Gnomad ASJ

AF:

0.704

Gnomad EAS

AF:

0.372

Gnomad SAS

AF:

0.522

Gnomad FIN

AF:

0.707

Gnomad MID

AF:

0.547

Gnomad NFE

AF:

0.734

Gnomad OTH

AF:

0.590

GnomAD2 exomes

AF:

0.610

AC:

153053

AN:

250886

AF XY:

0.622

show subpopulations

Gnomad AFR exome

AF:

0.293

Gnomad AMR exome

AF:

0.467

Gnomad ASJ exome

AF:

0.707

Gnomad EAS exome

AF:

0.361

Gnomad FIN exome

AF:

0.715

Gnomad NFE exome

AF:

0.728

Gnomad OTH exome

AF:

0.653

GnomAD4 exome

AF:

0.686

AC:

996065

AN:

1452780

Hom.:

350053

Cov.:

AF XY:

0.684

AC XY:

494939

AN XY:

723260

show subpopulations

African (AFR)

AF:

0.277

AC:

9218

AN:

33324

American (AMR)

AF:

0.480

AC:

21458

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.705

AC:

18382

AN:

26090

East Asian (EAS)

AF:

0.368

AC:

14598

AN:

39676

South Asian (SAS)

AF:

0.539

AC:

46406

AN:

86060

European-Finnish (FIN)

AF:

0.720

AC:

38379

AN:

53298

Middle Eastern (MID)

AF:

0.570

AC:

2734

AN:

4796

European-Non Finnish (NFE)

AF:

0.729

AC:

805697

AN:

1104762

Other (OTH)

AF:

0.653

AC:

39193

AN:

60056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

15113

30226

45340

60453

75566

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19518

39036

58554

78072

97590

<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:

0.573

AC:

87149

AN:

151980

Hom.:

27839

Cov.:

AF XY:

0.569

AC XY:

42249

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.296

AC:

12232

AN:

41394

American (AMR)

AF:

0.562

AC:

8574

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.704

AC:

2440

AN:

3466

East Asian (EAS)

AF:

0.373

AC:

1926

AN:

5168

South Asian (SAS)

AF:

0.522

AC:

2516

AN:

4822

European-Finnish (FIN)

AF:

0.707

AC:

7483

AN:

10582

Middle Eastern (MID)

AF:

0.544

AC:

160

AN:

294

European-Non Finnish (NFE)

AF:

0.734

AC:

49887

AN:

67966

Other (OTH)

AF:

0.594

AC:

1255

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1650

3301

4951

6602

8252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

724

1448

2172

2896

3620

<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:

0.651

Hom.:

27745

Bravo

AF:

0.547

Asia WGS

AF:

0.465

AC:

1621

AN:

3478

EpiCase

AF:

0.730

EpiControl

AF:

0.724

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

- -

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

- -

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

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

- -

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

- -

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

- -

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

-0.72

CADD

Benign

4.3

(source)

DANN

Benign

0.44

PhyloP100

-3.2

Mutation Taster

=100/0

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