rs61735353

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_002470.4(MYH3):c.3009G>A(p.Ala1003Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,614,082 control chromosomes in the GnomAD database, including 210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 17 hom., cov: 32)

Exomes 𝑓: 0.015 ( 193 hom. )

Consequence

MYH3
NM_002470.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.470

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 17-10639391-C-T is Benign according to our data. Variant chr17-10639391-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.47 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0119 (1817/152286) while in subpopulation NFE AF = 0.0159 (1084/68016). AF 95% confidence interval is 0.0151. There are 17 homozygotes in GnomAd4. There are 885 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MYH3	NM_002470.4 link	c.3009G>A	p.Ala1003Ala	synonymous_variant	Exon 24 of 41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4 link	c.3009G>A	p.Ala1003Ala	synonymous_variant	Exon 24 of 41		XP_011522172.1
MYH3	XM_011523871.3 link	c.3009G>A	p.Ala1003Ala	synonymous_variant	Exon 24 of 41		XP_011522173.1
MYH3	XM_047436127.1 link	c.3009G>A	p.Ala1003Ala	synonymous_variant	Exon 26 of 43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MYH3	ENST00000583535.6 link	c.3009G>A	p.Ala1003Ala	synonymous_variant	Exon 24 of 41	5	NM_002470.4	ENSP00000464317.1
MYHAS	ENST00000579914.2 link	n.705+25514C>T		intron_variant	Intron 4 of 4	4
MYHAS	ENST00000584139.2 link	n.1041+25514C>T		intron_variant	Intron 7 of 8	3

Frequencies

GnomAD3 genomes

AF:

0.0120

AC:

1819

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00565

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.00779

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0248

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0160

Gnomad OTH

AF:

0.0119

GnomAD2 exomes

AF:

0.0122

AC:

3071

AN:

251226

AF XY:

0.0120

show subpopulations

Gnomad AFR exome

AF:

0.00591

Gnomad AMR exome

AF:

0.00509

Gnomad ASJ exome

AF:

0.0204

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0290

Gnomad NFE exome

AF:

0.0162

Gnomad OTH exome

AF:

0.0152

GnomAD4 exome

AF:

0.0149

AC:

21816

AN:

1461796

Hom.:

193

Cov.:

AF XY:

0.0143

AC XY:

10427

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.00493

AC:

165

AN:

33476

American (AMR)

AF:

0.00532

AC:

238

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

505

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00101

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.0302

AC:

1613

AN:

53416

Middle Eastern (MID)

AF:

0.00590

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0165

AC:

18322

AN:

1111954

Other (OTH)

AF:

0.0141

AC:

851

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

1242

2484

3725

4967

6209

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

678

1356

2034

2712

3390

<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:

0.0119

AC:

1817

AN:

152286

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

885

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00565

AC:

235

AN:

41558

American (AMR)

AF:

0.00778

AC:

119

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0248

AC:

263

AN:

10620

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0159

AC:

1084

AN:

68016

Other (OTH)

AF:

0.0118

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

188

283

377

471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0151

Hom.:

Bravo

AF:

0.0106

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0154

EpiControl

AF:

0.0138

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 30, 2020

GeneDx

Significance:Likely 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

-0.37

CADD

Benign

(source)

DANN

Benign

0.47

PhyloP100

0.47

Mutation Taster

=71/29

polymorphism

(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