NM_002470.4:c.5254G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002470.4(MYH3):c.5254G>A(p.Ala1752Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0203 in 1,614,110 control chromosomes in the GnomAD database, including 358 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1752S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.022 ( 34 hom., cov: 32)

Exomes 𝑓: 0.020 ( 324 hom. )

Consequence

MYH3
NM_002470.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.88

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:

LOC124903927 (HGNC:):

LOC124903927 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 (MetaRNN=0.0059009492).

BP6

Variant 17-10631643-C-T is Benign according to our data. Variant chr17-10631643-C-T is described in ClinVar as [Benign]. Clinvar id is 129664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0218 (3323/152254) while in subpopulation AFR AF = 0.0309 (1284/41542). AF 95% confidence interval is 0.0295. There are 34 homozygotes in GnomAd4. There are 1590 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 34 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4 link	c.5254G>A	p.Ala1752Thr	missense_variant	Exon 36 of 41	ENST00000583535.6	NP_002461.2	P11055Q5GJ67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYH3	ENST00000583535.6 link	c.5254G>A	p.Ala1752Thr	missense_variant	Exon 36 of 41	5	NM_002470.4	ENSP00000464317.1	P11055
MYHAS	ENST00000579914.2 link	n.705+17766C>T		intron_variant	Intron 4 of 4	4
MYHAS	ENST00000584139.2 link	n.1041+17766C>T		intron_variant	Intron 7 of 8	3
MYHAS	ENST00000781814.1 link	n.165-3042C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0218

AC:

3317

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0310

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0131

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00269

Gnomad SAS

AF:

0.0269

Gnomad FIN

AF:

0.0191

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0209

Gnomad OTH

AF:

0.0210

GnomAD2 exomes

AF:

0.0179

AC:

4507

AN:

251184

AF XY:

0.0186

show subpopulations

Gnomad AFR exome

AF:

0.0299

Gnomad AMR exome

AF:

0.00764

Gnomad ASJ exome

AF:

0.00873

Gnomad EAS exome

AF:

0.000870

Gnomad FIN exome

AF:

0.0172

Gnomad NFE exome

AF:

0.0201

Gnomad OTH exome

AF:

0.0184

GnomAD4 exome

AF:

0.0202

AC:

29524

AN:

1461856

Hom.:

324

Cov.:

AF XY:

0.0204

AC XY:

14864

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.0284

AC:

951

AN:

33478

American (AMR)

AF:

0.00769

AC:

344

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00838

AC:

219

AN:

26136

East Asian (EAS)

AF:

0.00589

AC:

234

AN:

39700

South Asian (SAS)

AF:

0.0287

AC:

2473

AN:

86246

European-Finnish (FIN)

AF:

0.0165

AC:

883

AN:

53420

Middle Eastern (MID)

AF:

0.00745

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0209

AC:

23221

AN:

1111994

Other (OTH)

AF:

0.0191

AC:

1156

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1881

3762

5643

7524

9405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0218

AC:

3323

AN:

152254

Hom.:

Cov.:

AF XY:

0.0214

AC XY:

1590

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0309

AC:

1284

AN:

41542

American (AMR)

AF:

0.0131

AC:

200

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3468

East Asian (EAS)

AF:

0.00270

AC:

AN:

5186

South Asian (SAS)

AF:

0.0272

AC:

131

AN:

4822

European-Finnish (FIN)

AF:

0.0191

AC:

203

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0209

AC:

1422

AN:

68008

Other (OTH)

AF:

0.0222

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

159

317

476

634

793

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0196

Hom.:

105

Bravo

AF:

0.0209

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0223

AC:

ESP6500AA

AF:

0.0293

AC:

129

ESP6500EA

AF:

0.0202

AC:

174

ExAC

AF:

0.0192

AC:

2327

Asia WGS

AF:

0.0360

AC:

125

AN:

3478

EpiCase

AF:

0.0207

EpiControl

AF:

0.0180

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYH3: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29687901, 30967136, 22519952, 32315303) -

not specified

Benign:3

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. -

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

- -

Freeman-Sheldon syndrome

Benign:1

Jan 12, 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 12, 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

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.63

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0059

MetaSVM

Uncertain

-0.14

MutationAssessor

Uncertain

2.7

PhyloP100

4.9

PrimateAI

Uncertain

0.62

Sift4G

Benign

0.080

Polyphen

0.29

Vest4

0.16

MPC

0.31

ClinPred

0.017

GERP RS

5.0

Varity_R

0.23

gMVP

0.80

Mutation Taster

=94/6

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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NM_002470.4:c.5254G>A

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