MYH9
protein-codingmyosin heavy chain 9, the group of Myosin heavy chains, class II|MicroRNA protein coding host genes
Gene summary
This gene encodes a conventional non-muscle myosin; this protein should not be confused with the unconventional myosin-9a or 9b (MYO9A or MYO9B). The encoded protein is a myosin IIA heavy chain that contains an IQ domain and a myosin head-like domain which is involved in several important functions, including cytokinesis, cell motility and maintenance of cell shape. Defects in this gene have been associated with non-syndromic sensorineural deafness autosomal dominant type 17, Epstein syndrome, Alport syndrome with macrothrombocytopenia, Sebastian syndrome, Fechtner syndrome and macrothrombocytopenia with progressive sensorineural deafness. [provided by RefSeq, Dec 2011]
- DFNA17
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~106.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0019587
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011350
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0011350
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0015912
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015912
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007954
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0015912
Submitter: ClinGen
The MYH9 gene definitively causes MYH9-Related Disorders, a class of autosomal dominant disorders characterized by congenital macrothrombocytopenia and variable leucocyte inclusion bodies, renal abnormalities, cataracts, and progressive sensorineural hearing loss. This association was assessed using the ClinGen Clinical Validity Framework as of 12/11/2017. Recent reviews report that missense variants are located at only 21 of the 1,960 amino acid residues of the protein (Balduini 2011, De Rocco 2013, Pecci 2014). Nonsense or frameshift variants of MYH9 have only been reported in the last exon of the gene. A genotype-phenotype correlation has been shown repeatedly (Dong 2005, Pecci 2008, Pecci 2014, Saposnik 2014). There are several reports of the p.Arg705His variant in MYH9 causing nonsyndromic hearing loss, DFNA17 (Lalwani 2000, Hildebrand 2006). However, no testing for the blood phenotype was reported in any affected individuals in these families, and at least two other individuals with the hematological features of MYH9-RD had the same variant (Verver 2015). These data suggest nonsyndromic hearing loss may not be a distinct entity from MYH9-RD. Hearing loss is not a fully penetrant feature of MYH9-RD; a review of cases indicated approximately 48% of patients have hearing loss (Pecci 2014). Individuals presenting with nonsyndromic hearing loss who are found to have a pathogenic variant in MYH9 should be tested for the other phenotypes of MYH9-RD. In vitro functional evidence indicates that disease-causing variants may act through different molecular mechanisms in different cell types (Franke 2005, Hu 2002, Pecci 2005), exhibiting a dominant-negative effect on wild-type protein in granulocytes and haploinsufficiency in megakaryocytes and platelets (Pecci 2005). Four knock-in mouse models harboring 3 different human variants in MYH9 fully recapitulated the human phenotype of MYH9-RD (Zhang 2012, Suzuki 2013). In summary, MYH9 is definitively associated with AD MYH9-RD. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 2/20/2018.
Inheritance Pattern: AD
Disease ID:MONDO:0015912
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0015912
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Hematologic; Ophthalmologic; Renal
Intervention: Hematologic
Rationale: In active hemorrhage, DDAVP may decrease bleeding time; otherwise, platelet transfusion is necessary; Precautions related to bleeding risk may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MYH9 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002473.6. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 23 | 429 | 46 | 498 | ||
| missense | 9 | 52 | 665 | 231 | 18 | 975 |
| nonsense | 3 | 3 | 5 | 11 | ||
| start loss | 0 | |||||
| frameshift | 7 | 11 | 3 | 21 | ||
| splice donor/acceptor (+/-2bp) | 1 | 1 | 27 | 29 | ||
| Total | 20 | 67 | 723 | 660 | 64 | 1534 |
Highest pathogenic variant AF is 0.00066205394
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002464.1 | 40 | MANE Select | |
| Ensembl | ENSP00000216181.6 | 40 | MANE Select | |
| Ensembl | ENSP00000384631.1 | 5 | Standard | |
| Ensembl | ENSP00000414852.1 | 1 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| myh9b | Danio rerio | Structure: midbrain hindbrain boundary Quality: morphology abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Salmonella infection - Homo sapiens (human)
- Tight junction - Homo sapiens (human)
- Regulation of actin cytoskeleton - Homo sapiens (human)
- Primary Focal Segmental Glomerulosclerosis FSGS
- VEGFA-VEGFR2 Signaling Pathway
Biological Process
- meiotic spindle organization
- angiogenesis
- in utero embryonic development
- establishment of T cell polarity
- membrane protein ectodomain proteolysis
Molecular Function
- microfilament motor activity
- RNA binding
- motor activity
- actin binding
- integrin binding
Cellular Component
- stress fiber
- ruffle
- immunological synapse
- uropod
- nucleus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000216181
- Coding exons
- 40
- Length
- 106737
- Individuals with no LoFs
- 125740
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 8
- Defined
- 125748
- p
- 0.0000318
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.47 | 820 | 1.15e+3 | 0.712 | 0.0000835 | 12926 |
| Missense (PolyPhen) | 236 | 460.87 | 0.51207 | 5059 | ||
| Synonymous | -3.16 | 594 | 504 | 1.18 | 0.0000382 | 3640 |
| Loss of Function | 9.11 | 4 | 104 | 0.0383 | 0.00000540 | 1253 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000044 | 0.000044 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping. During cell spreading, plays an important role in cytoskeleton reorganization, focal contacts formation (in the margins but not the central part of spreading cells), and lamellipodial retraction; this function is mechanically antagonized by MYH10. {ECO:0000269|PubMed:20052411}.;
- Disease
- DISEASE: Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss (MATINS) [MIM:155100]: An autosomal dominant disorder characterized by thrombocytopenia, giant platelets and Dohle body-like inclusions in peripheral blood leukocytes with variable ultrastructural appearance. Some affected individuals lack leukocyte inclusion bodies on classic staining of peripheral blood smears. Alport syndrome-like features of nephritis, hearing loss, and eye abnormalities are present in some patients. {ECO:0000269|PubMed:10973259, ECO:0000269|PubMed:10973260, ECO:0000269|PubMed:11590545, ECO:0000269|PubMed:11752022, ECO:0000269|PubMed:11776386, ECO:0000269|PubMed:11935325, ECO:0000269|PubMed:12533692, ECO:0000269|PubMed:12621333, ECO:0000269|PubMed:12649151, ECO:0000269|PubMed:12792306, ECO:0000269|PubMed:16969870}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal dominant, 17 (DFNA17) [MIM:603622]: A form of deafness characterized by progressive high frequency hearing impairment and cochleosaccular degeneration. {ECO:0000269|PubMed:11023810}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Subjects with mutations in the motor domain of MYH9 present with severe thrombocytopenia and develop nephritis and deafness before the age of 40 years, while those with mutations in the tail domain have a much lower risk of noncongenital complications and significantly higher platelet counts. The clinical course of patients with mutations in the four most frequently affected residues of MYH9 (responsible for 70% of MYH9- related cases) were evaluated. Mutations at residue 1933 do not induce kidney damage or cataracts and cause deafness only in the elderly, those in position 702 result in severe thrombocytopenia and produce nephritis and deafness at a juvenile age, while alterations at residue 1424 or 1841 result in intermediate clinical pictures.; DISEASE: Note=Genetic variations in MYH9 are associated with non- diabetic end stage renal disease (ESRD).;
Recessive Scores
- pRec
- 0.644
Intolerance Scores
- LoFtool
- 0.00606
- RVIS EVS
- -1.99
- RVIS percentile EVS
- 1.75
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- S
- Essential (gene trap)
- K
- Indispensability pred.
- E
- Indispensability score
- 0.965
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |