MYH3

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

Basic information

Region (hg38): 17:10628525-10657309

Links

ENSG00000109063 ∙ NCBI:4621 ∙ OMIM:160720 ∙ HGNC:7573 ∙ Uniprot:P11055 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Freeman-Sheldon syndrome (Definitive), mode of inheritance: AD
• Freeman-Sheldon syndrome (Moderate), mode of inheritance: AD
• contractures, pterygia, and variable skeletal fusions syndrome 1B (Moderate), mode of inheritance: AR
• digitotalar dysmorphism (Supportive), mode of inheritance: AD
• Sheldon-hall syndrome (Supportive), mode of inheritance: AD
• Freeman-Sheldon syndrome (Supportive), mode of inheritance: AD
• autosomal recessive multiple pterygium syndrome (Supportive), mode of inheritance: AR
• spondylocarpotarsal synostosis syndrome (Supportive), mode of inheritance: AR
• contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A (Supportive), mode of inheritance: AD
• contractures, pterygia, and variable skeletal fusions syndrome 1B (Strong), mode of inheritance: AR
• distal arthrogryposis type 2B1 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Arthrogryposis, distal, type 2A; Arthyrgryposis, distal, type 2B3; Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A; Contractures, pterygia, and variable skeletal fusions syndrome 1B	AD	General	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	Craniofacial; Musculoskeletal	21032118; 4975238; 5467037; 4220006; 7039311; 2803721; 9138511; 4220006; 16510655; 16642020; 18695058; 19309503; 19571066; 19684571; 20924721; 21531865; 25957469; 29625835; 29805041

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MYH3 gene.

• not provided (1086 variants)
• Freeman-Sheldon syndrome (182 variants)
• Distal arthrogryposis type 2B1 (158 variants)
• not specified (84 variants)
• Inborn genetic diseases (61 variants)
• Arthrogryposis, distal, type 2B3 (35 variants)
• Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A (34 variants)
• Contractures, pterygia, and variable skeletal fusions syndrome 1B (29 variants)
• MYH3-related condition (18 variants)
• MYH3-Related Disorders (12 variants)
• Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A;Spondylocarpotarsal synostosis syndrome (6 variants)
• Arthrogryposis multiplex congenita (6 variants)
• Distal arthrogryposis (4 variants)
• Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A;Freeman-Sheldon syndrome;Arthrogryposis, distal, type 2B3;Contractures, pterygia, and variable skeletal fusions syndrome 1B (2 variants)
• Spondylocarpotarsal synostosis syndrome (2 variants)
• - (2 variants)
• Freeman-Sheldon syndrome;Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A;Distal arthrogryposis type 2B1 (1 variants)
• Freeman-Sheldon syndrome;Arthrogryposis, distal, type 2B3 (1 variants)
• Rhabdomyolysis (1 variants)
• Freeman-Sheldon syndrome;Arthrogryposis, distal, type 2B3;Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A;Contractures, pterygia, and variable skeletal fusions syndrome 1B (1 variants)
• See cases (1 variants)
• Freeman-Sheldon syndrome;Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A;Contractures, pterygia, and variable skeletal fusions syndrome 1B;Arthrogryposis, distal, type 2B3 (1 variants)
• Seizure (1 variants)
• Flexion contracture;Seizure (1 variants)
• Malignant tumor of prostate (1 variants)
• Arthrogryposis, distal, type 1A (1 variants)
• Arthrogryposis, distal, type 2B3;Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A;Freeman-Sheldon syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MYH3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			10	233	16	259
missense	5	19	454	22	4	504
nonsense	16	3				19
start loss						0
frameshift	10	4	2			16
inframe indel		2	5			7
splice donor/acceptor (+/-2bp)	2	12	3			17
splice region			34	42	5	81
non coding	1		8	127	93	229
Total	34	40	482	382	113

Highest pathogenic variant AF is 0.0000132

Variants in MYH3

This is a list of pathogenic ClinVar variants found in the MYH3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
17-10628614-C-T		Freeman-Sheldon syndrome • Distal arthrogryposis type 2B1	Conflicting classifications of pathogenicity (Jan 13, 2018)
17-10628622-A-C		Distal arthrogryposis type 2B1 • Freeman-Sheldon syndrome	Conflicting classifications of pathogenicity (Jan 12, 2018)
17-10628648-C-G		MYH3-related disorder	Likely benign (Jun 13, 2022)
17-10628661-C-T			Uncertain significance (Jan 04, 2024)
17-10628667-C-T			Uncertain significance (Jun 04, 2023)
17-10628668-G-A			Likely benign (Nov 27, 2023)
17-10628672-A-G		Freeman-Sheldon syndrome • Distal arthrogryposis type 2B1	Uncertain significance (Jan 13, 2018)
17-10628676-C-T			Uncertain significance (Jul 29, 2022)
17-10628683-G-A			Likely benign (Nov 13, 2023)
17-10628691-G-C		Freeman-Sheldon syndrome • Distal arthrogryposis type 2B1	Benign/Likely benign (Jan 18, 2024)
17-10628692-T-C			Likely benign (Apr 07, 2022)
17-10628693-A-G			Likely benign (Mar 02, 2023)
17-10628892-C-G			Benign (Apr 03, 2021)
17-10628938-G-A			Likely benign (Jul 09, 2020)
17-10629351-A-C			Benign (Dec 13, 2019)
17-10629464-A-G			Likely benign (Nov 04, 2019)
17-10629564-TG-T		not specified	Benign/Likely benign (Apr 03, 2021)
17-10629567-G-A		not specified • Freeman-Sheldon syndrome • Arthrogryposis, distal, type 2B3 • Contractures, pterygia, and variable skeletal fusions syndrome 1B • Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A	Benign (Sep 05, 2021)
17-10629568-G-C		not specified	Likely benign (-)
17-10629580-C-T			Likely benign (Jan 04, 2024)
17-10629581-C-A			Likely benign (Jan 25, 2023)
17-10629585-T-C			Benign (Jan 22, 2024)
17-10629589-C-A			Likely benign (Oct 24, 2023)
17-10629589-C-T			Likely benign (Dec 10, 2023)
17-10629605-A-T			Uncertain significance (Jan 15, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MYH3	protein_coding	protein_coding	ENST00000583535	39	28784

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
6.72e-21	1.00	125633	0	115	125748	0.000457

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.74	855	1.01e+3	0.846	0.0000639	12870
Missense in Polyphen		306	449.73	0.68041		5848
Synonymous	-0.966	447	422	1.06	0.0000290	3555
Loss of Function	4.70	51	102	0.499	0.00000604	1265

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00109	0.00109
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000326	0.000326
Finnish	0.000231	0.000231
European (Non-Finnish)	0.000458	0.000457
Middle Eastern	0.000326	0.000326
South Asian	0.000327	0.000327
Other	0.00163	0.00163

dbNSFP

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.
• Pathway: Tight junction - Homo sapiens (human);Striated Muscle Contraction;Striated Muscle Contraction;Muscle contraction (Consensus)

Recessive Scores

• pRec: 0.212

Intolerance Scores

• loftool: 0.112
• rvis_EVS: -1.55
• rvis_percentile_EVS: 3.23

Haploinsufficiency Scores

• pHI: 0.431
• hipred: Y
• hipred_score: 0.740
• ghis: 0.402

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.261

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Myh3

Gene ontology

• Biological process: skeletal muscle contraction;protein dephosphorylation;muscle organ development;actin filament-based movement;muscle filament sliding;embryonic limb morphogenesis;sarcomere organization;ATP metabolic process;face morphogenesis
• Cellular component: cytosol;muscle myosin complex;sarcomere;myosin filament;extracellular exosome
• Molecular function: microfilament motor activity;calmodulin binding;ATP binding;myosin phosphatase activity;ATPase activity, coupled;actin filament binding