rs61735358

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.3592G>A(p.Ala1198Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00831 in 1,613,956 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1198V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0062 ( 6 hom., cov: 31)

Exomes 𝑓: 0.0085 ( 70 hom. )

Consequence

MYH3
NM_002470.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 4.97

Publications

14 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 (MetaRNN=0.013158917).

BP6

Variant 17-10638180-C-T is Benign according to our data. Variant chr17-10638180-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00625 (950/152072) while in subpopulation NFE AF = 0.0104 (704/68004). AF 95% confidence interval is 0.00972. There are 6 homozygotes in GnomAd4. There are 433 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002470.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	NM_002470.4	MANE Select	c.3592G>A	p.Ala1198Thr	missense	Exon 27 of 41	NP_002461.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYH3	ENST00000583535.6	TSL:5 MANE Select	c.3592G>A	p.Ala1198Thr	missense	Exon 27 of 41	ENSP00000464317.1
MYHAS	ENST00000579914.2	TSL:4	n.705+24303C>T		intron	N/A
MYHAS	ENST00000584139.2	TSL:3	n.1041+24303C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00625

AC:

950

AN:

151954

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00617

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00530

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00637

AC:

1603

AN:

251480

AF XY:

0.00627

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00312

Gnomad ASJ exome

AF:

0.000694

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00702

Gnomad NFE exome

AF:

0.0108

Gnomad OTH exome

AF:

0.00635

GnomAD4 exome

AF:

0.00852

AC:

12460

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00820

AC XY:

5965

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00152

AC:

AN:

33480

American (AMR)

AF:

0.00318

AC:

142

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000459

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00151

AC:

130

AN:

86258

European-Finnish (FIN)

AF:

0.00749

AC:

400

AN:

53414

Middle Eastern (MID)

AF:

0.00850

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0101

AC:

11228

AN:

1112008

Other (OTH)

AF:

0.00742

AC:

448

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

953

1907

2860

3814

4767

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

420

840

1260

1680

2100

<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:

0.00625

AC:

950

AN:

152072

Hom.:

Cov.:

AF XY:

0.00583

AC XY:

433

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

41496

American (AMR)

AF:

0.00616

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00125

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00530

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0104

AC:

704

AN:

68004

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

104

155

207

259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00863

Hom.:

Bravo

AF:

0.00593

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0105

AC:

ExAC

AF:

0.00676

AC:

821

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00987

EpiControl

AF:

0.0105

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

not specified (4)

Distal arthrogryposis type 2B1 (1)

Freeman-Sheldon syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Benign

0.052

Eigen_PC

Benign

0.099

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.78

MetaRNN

Benign

0.013

MetaSVM

Uncertain

-0.23

MutationAssessor

Uncertain

2.3

PhyloP100

5.0

PrimateAI

Uncertain

0.50

Sift4G

Benign

0.31

Polyphen

0.089

Vest4

0.19

MVP

0.68

MPC

0.39

ClinPred

0.026

GERP RS

5.5

Varity_R

0.11

gMVP

0.19

Mutation Taster

=91/9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over