rs2285477

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_002470.4(MYH3):c.3574G>A(p.Ala1192Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.749 in 1,613,298 control chromosomes in the GnomAD database, including 460,038 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.69 ( 37317 hom., cov: 27)

Exomes 𝑓: 0.75 ( 422721 hom. )

Consequence

MYH3
NM_002470.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.761

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in the MYH3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. Gene score misZ: 1.7445 (below the threshold of 3.09). Trascript score misZ: 4.649 (above the threshold of 3.09). GenCC associations: The gene is linked to spondylocarpotarsal synostosis syndrome, contractures, pterygia, and variable skeletal fusions syndrome 1B, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, digitotalar dysmorphism, autosomal recessive multiple pterygium syndrome, Freeman-Sheldon syndrome, distal arthrogryposis type 2B1, Sheldon-hall syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=8.30933E-6).

BP6

Variant 17-10638198-C-T is Benign according to our data. Variant chr17-10638198-C-T is described in ClinVar as [Benign]. Clinvar id is 129658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10638198-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.79 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4 link	c.3574G>A	p.Ala1192Thr	missense_variant	Exon 27 of 41	ENST00000583535.6	NP_002461.2	P11055Q5GJ67
MYH3	XM_011523870.4 link	c.3574G>A	p.Ala1192Thr	missense_variant	Exon 27 of 41		XP_011522172.1	P11055
MYH3	XM_011523871.3 link	c.3574G>A	p.Ala1192Thr	missense_variant	Exon 27 of 41		XP_011522173.1	P11055
MYH3	XM_047436127.1 link	c.3574G>A	p.Ala1192Thr	missense_variant	Exon 29 of 43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6 link	c.3574G>A	p.Ala1192Thr	missense_variant	Exon 27 of 41	5	NM_002470.4	ENSP00000464317.1		P11055

Frequencies

GnomAD3 genomes

AF:

0.693

AC:

104795

AN:

151322

Hom.:

37289

Cov.:

show subpopulations

Gnomad AFR

AF:

0.567

Gnomad AMI

AF:

0.793

Gnomad AMR

AF:

0.648

Gnomad ASJ

AF:

0.752

Gnomad EAS

AF:

0.380

Gnomad SAS

AF:

0.613

Gnomad FIN

AF:

0.742

Gnomad MID

AF:

0.636

Gnomad NFE

AF:

0.796

Gnomad OTH

AF:

0.689

GnomAD3 exomes

AF:

0.687

AC:

172652

AN:

251444

Hom.:

61461

AF XY:

0.695

AC XY:

94404

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.568

Gnomad AMR exome

AF:

0.556

Gnomad ASJ exome

AF:

0.755

Gnomad EAS exome

AF:

0.374

Gnomad SAS exome

AF:

0.631

Gnomad FIN exome

AF:

0.749

Gnomad NFE exome

AF:

0.789

Gnomad OTH exome

AF:

0.719

GnomAD4 exome

AF:

0.755

AC:

1103404

AN:

1461860

Hom.:

422721

Cov.:

109

AF XY:

0.753

AC XY:

547392

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.553

Gnomad4 AMR exome

AF:

0.568

Gnomad4 ASJ exome

AF:

0.753

Gnomad4 EAS exome

AF:

0.382

Gnomad4 SAS exome

AF:

0.630

Gnomad4 FIN exome

AF:

0.754

Gnomad4 NFE exome

AF:

0.794

Gnomad4 OTH exome

AF:

0.728

GnomAD4 genome

AF:

0.693

AC:

104876

AN:

151438

Hom.:

37317

Cov.:

AF XY:

0.685

AC XY:

50617

AN XY:

73936

show subpopulations

Gnomad4 AFR

AF:

0.567

Gnomad4 AMR

AF:

0.648

Gnomad4 ASJ

AF:

0.752

Gnomad4 EAS

AF:

0.381

Gnomad4 SAS

AF:

0.612

Gnomad4 FIN

AF:

0.742

Gnomad4 NFE

AF:

0.796

Gnomad4 OTH

AF:

0.694

Alfa

AF:

0.752

Hom.:

68998

Bravo

AF:

0.676

TwinsUK

AF:

0.804

AC:

2981

ALSPAC

AF:

0.791

AC:

3048

ESP6500AA

AF:

0.574

AC:

2529

ESP6500EA

AF:

0.789

AC:

6787

ExAC

AF:

0.690

AC:

83758

Asia WGS

AF:

0.545

AC:

1901

AN:

3478

EpiCase

AF:

0.789

EpiControl

AF:

0.782

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 05, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 32315303) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Freeman-Sheldon syndrome

Benign:2

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. -

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

- -

Arthrogryposis, distal, type 2B3

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 12, 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

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

2.2

DANN

Benign

0.97

DEOGEN2

Benign

0.30

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.50

MetaRNN

Benign

0.0000083

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.95

PrimateAI

Benign

0.31

Sift4G

Benign

0.52

Polyphen

0.014

Vest4

0.0080

MPC

0.25

ClinPred

0.0016

GERP RS

-2.1

Varity_R

0.027

gMVP

0.15

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over