rs12941197

Variant names:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_002470.4(MYH3):c.3409C>T(p.Arg1137Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,607,938 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0037 ( 15 hom. )

Consequence

MYH3
NM_002470.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.23

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 -15 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=0.014895111).

BP6

Variant 17-10638363-G-A is Benign according to our data. Variant chr17-10638363-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 258680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10638363-G-A is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 359 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4 link	c.3409C>T	p.Arg1137Cys	missense_variant	Exon 27 of 41	ENST00000583535.6	NP_002461.2	P11055Q5GJ67
MYH3	XM_011523870.4 link	c.3409C>T	p.Arg1137Cys	missense_variant	Exon 27 of 41		XP_011522172.1	P11055
MYH3	XM_011523871.3 link	c.3409C>T	p.Arg1137Cys	missense_variant	Exon 27 of 41		XP_011522173.1	P11055
MYH3	XM_047436127.1 link	c.3409C>T	p.Arg1137Cys	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.3409C>T	p.Arg1137Cys	missense_variant	Exon 27 of 41	5	NM_002470.4	ENSP00000464317.1		P11055

Frequencies

GnomAD3 genomes

AF:

0.00236

AC:

359

AN:

151944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000677

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000525

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00227

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00422

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00256

AC:

631

AN:

246366

Hom.:

AF XY:

0.00264

AC XY:

353

AN XY:

133680

show subpopulations

Gnomad AFR exome

AF:

0.000560

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00147

Gnomad FIN exome

AF:

0.00219

Gnomad NFE exome

AF:

0.00450

Gnomad OTH exome

AF:

0.00247

GnomAD4 exome

AF:

0.00372

AC:

5415

AN:

1455876

Hom.:

Cov.:

AF XY:

0.00371

AC XY:

2688

AN XY:

724536

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00170

Gnomad4 FIN exome

AF:

0.00227

Gnomad4 NFE exome

AF:

0.00447

Gnomad4 OTH exome

AF:

0.00242

GnomAD4 genome

AF:

0.00236

AC:

359

AN:

152062

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

168

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.000675

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.00167

Gnomad4 FIN

AF:

0.00227

Gnomad4 NFE

AF:

0.00422

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00347

Hom.:

Bravo

AF:

0.00193

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00294

AC:

357

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00322

EpiControl

AF:

0.00379

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

Mar 12, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYH3: BS2 -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Freeman-Sheldon syndrome

Benign:1

May 03, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Freeman-Sheldon syndrome;C1867440:Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A;C5193098:Arthrogryposis, distal, type 2B3;C5193114:Contractures, pterygia, and variable skeletal fusions syndrome 1B

Benign:1

Aug 26, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Distal arthrogryposis type 2B1

Benign:1

May 03, 2017

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

Uncertain

0.34

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.68

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.015

MetaSVM

Pathogenic

0.83

MutationAssessor

Pathogenic

4.3

PrimateAI

Uncertain

0.56

Sift4G

Uncertain

0.019

Polyphen

1.0

Vest4

0.32

MVP

0.90

MPC

0.34

ClinPred

0.076

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.50

gMVP

0.53

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