GeneBe

MYH3

protein-coding

myosin heavy chain 3, the group of Myosin heavy chains, class II

Gene summary

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]

MANE transcript

NM_002470.4

Inheritance

AR, AD

ClinVar variants

P:142U:900B:463

Top phenotype

Arthrogryposis, distal, type 2A; Arthyrgryposis, distal, type 2B3; Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A; Contractures, pterygia, and variable skeletal fusions syndrome 1B

gnomAD constraint

pLI —, LoF o/e 0.5

Max pathogenic AF

—

Genomic locus

chr17:10,628,526-10,657,309

External References & Databases

Ensembl (ENSG00000109063)NCBI Gene (4621)OMIM (160720)HGNC:7573GenCCUniProt (P11055)AlphaFoldClinVar (MYH3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~28.8 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

contractures, pterygia, and variable skeletal fusions syndrome 1BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020746

Submitter: G2P

distal arthrogryposis type 2B1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020820

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive multiple pterygium syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009926

Submitter: Orphanet

arthrogryposisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008779

Submitter: PanelApp Australia

contractures, pterygia, and variable skeletal fusions syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020937

Submitter: PanelApp Australia

Sheldon-hall syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011128

Submitter: Orphanet

spondylocarpotarsal synostosis syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010094

Submitter: Orphanet

Freeman-Sheldon syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008675

Submitter: G2P

Freeman-Sheldon syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008675

Submitter: Orphanet

Freeman-Sheldon syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008675

Submitter: Ambry Genetics

digitotalar dysmorphismSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015240

Submitter: Orphanet

contractures, pterygia, and spondylocarpotarsal fusion syndrome 1ASUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008338

Submitter: Orphanet

contractures, pterygia, and variable skeletal fusions syndrome 1BMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0020746

Submitter: Ambry Genetics

contractures, pterygia, and variable skeletal fusions syndrome 1BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020746

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Arthrogryposis, distal, type 2A; Arthyrgryposis, distal, type 2B3; Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A; Contractures, pterygia, and variable skeletal fusions syndrome 1BAD

Manifestation: Craniofacial; Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 21032118; 4975238; 5467037; 4220006; 7039311; 2803721; 9138511; 4220006; 16510655; 16642020; 18695058; 19309503; 19571066; 19684571; 20924721; 21531865; 25957469; 29625835; 29805041Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MYH3 variants in ClinVar

24 Conditions Cataloged
not providedTotal: 1636
Inborn genetic diseasesTotal: 236
not specifiedTotal: 201
Freeman-Sheldon syndromeTotal: 175
MYH3-related disorderTotal: 148
Distal arthrogryposis type 2B1Total: 137
Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1ATotal: 47
Arthrogryposis, distal, type 2B3Total: 46

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002470.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
17
clinvar
403
clinvar
4
clinvar
 424
missense
8
clinvar
42
clinvar
867
clinvar
54
clinvar
2
clinvar
 973
nonsense
26
clinvar
9
clinvar
1
clinvar
 36
start loss
0
frameshift
17
clinvar
18
clinvar
3
clinvar
 38
splice donor/acceptor (+/-2bp)
3
clinvar
19
clinvar
12
clinvar
 34
Total548890045761505

Highest pathogenic variant AF is 0.0011354537

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002470.4RefSeqNP_002461.239MANE Select
ENST00000583535.6EnsemblENSP00000464317.139MANE Select
ENST00000961194.1EnsemblENSP00000631253.139Standard
ENST00000961194.2EnsemblENSP00000631253.139Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Tight junction - Homo sapiens (human)
  • Striated Muscle Contraction
  • Striated Muscle Contraction
  • Muscle contraction

Biological Process

  • skeletal muscle contraction
  • protein dephosphorylation
  • muscle organ development
  • actin filament-based movement
  • muscle filament sliding

Molecular Function

  • microfilament motor activity
  • calmodulin binding
  • ATP binding
  • myosin phosphatase activity
  • ATPase activity, coupled

Cellular Component

  • cytosol
  • muscle myosin complex
  • sarcomere
  • myosin filament
  • extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000583535
Coding exons
39
Length
28784
Individuals with no LoFs
125633
Homozygous LoFs
0
Heterozygous LoFs
115
Defined
125748
p
0.000457
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.748551.01e+30.8460.000063912870
Missense (PolyPhen)306449.730.680415848
Synonymous-0.9664474221.060.00002903555
Loss of Function4.70511020.4990.000006041265

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000370.00037rare
Latino/Admixed American0.000720.00072rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.000330.00033rare
Finnish0.000230.00023rare
European (Non-Finnish)0.000460.00046rare
South Asian0.000330.00033rare
Other0.00160.0016notable

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Muscle contraction.;
Disease
DISEASE: Arthrogryposis, distal, 2A (DA2A) [MIM:193700]: A form of distal arthrogryposis, a disease characterized by congenital joint contractures that mainly involve two or more distal parts of the limbs, in the absence of a primary neurological or muscle disease. DA2A is characterized by contractures of the hands and feet, oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice, puckered lips, and an H- shaped dimple of the chin. {ECO:0000269|PubMed:16642020}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Arthrogryposis, distal, 2B (DA2B) [MIM:601680]: A form of distal arthrogryposis, a disease characterized by congenital joint contractures that mainly involve two or more distal parts of the limbs, in the absence of a primary neurological or muscle disease. DA2B is characterized by contractures of the hands and feet, and a distinctive face characterized by prominent nasolabial folds, small mouth and downslanting palpebral fissures. {ECO:0000269|PubMed:16642020}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Arthrogryposis, distal, 8 (DA8) [MIM:178110]: A form of distal arthrogryposis, a disease characterized by congenital joint contractures that mainly involve two or more distal parts of the limbs, in the absence of a primary neurological or muscle disease. {ECO:0000269|PubMed:25957469}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.212

Intolerance Scores

LoFtool
0.112
RVIS EVS
-1.55
RVIS percentile EVS
3.23

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Indispensability pred.
N
Indispensability score
0.261

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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