MYO7A
protein-codingmyosin VIIA, the group of FERM domain containing|Myosin heavy chains, class VII|A-kinase anchoring proteins
Gene summary
This gene is a member of the myosin gene family. Myosins are mechanochemical proteins characterized by the presence of a motor domain, an actin-binding domain, a neck domain that interacts with other proteins, and a tail domain that serves as an anchor. This gene encodes an unconventional myosin with a very short tail. Defects in this gene are associated with the mouse shaker-1 phenotype and the human Usher syndrome 1B which are characterized by deafness, reduced vestibular function, and (in human) retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]
- USH1B
- DFNB2
- DFNA11
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~87.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0011032
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0010168
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0016484
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0700087
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0019588
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0019497
Submitter: ClinGen
The MYO7A gene has been associated with autosomal dominant nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 12/27/17. This association was made using case-level data. At least 8 missense variants and 1 deletion have been reported in humans. MYO7A was first associated with this disease in humans as early as 1997 (Liu et al.). Association is seen in at least 11 probands in 10 publications (9354784, 15300860, 15121790, 15221449, 16449806, 21150918, 23451214, 23383098, 28802369, 29400105). Variants in this gene segregated with disease in >50 additional family members. This gene-disease association is supported by a heterozygous mouse model, a protein interaction study and a biochemical function study. Of note, this gene has also been implicated in Usher syndrome. This has been assessed separately. In summary, MYO7A is definitively associated with autosomal dominant nonsyndromic hearing loss. 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 3/19/18.
Inheritance Pattern: AD
Disease ID:MONDO:0019587
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0010807
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0010168
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011032
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0010807
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0019497
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0010168
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0010807
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0700087
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011032
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0010168
Submitter: ClinGen
The MYO7A gene has been associated with autosomal recessive Usher syndrome type 1 using the ClinGen Clinical Validity Framework as of 6/28/2018. This association was made using case-level data only. At least 9 variants (missense, nonsense, frameshift, splice-site) have been reported in humans. MYO7A was first associated with this disease in humans as early as 1995 (Weil et al.). Association is seen in at least 8 probands in 3 publications (23559863, 18181211, 25211151). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. Of note, this gene has also been implicated in nonsyndromic hearing loss. This has been assessed separately. This gene-disease association is supported by relevant expression studies, protein interaction studies, and animal models that replicate the hearing loss phenotype. In summary, MYO7A is definitively associated with autosomal recessive Usher syndrome type 1.This classification was approved by the ClinGen Hearing Loss Working Group on 6/28/2018.
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Ophthalmologic
Intervention: Audiologic/Otolaryngologic
Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development
Comments: The timing of onset has been reported as highly variable, though heterozygous variants appear to result in postlingual onset
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MYO7A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000260.4. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 2 | 50 | 1210 | 7 | 1270 |
| missense | 28 | 209 | 1404 | 120 | 3 | 1764 |
| nonsense | 124 | 112 | 4 | 240 | ||
| start loss | 2 | 2 | ||||
| frameshift | 189 | 138 | 5 | 332 | ||
| splice donor/acceptor (+/-2bp) | 52 | 107 | 5 | 1 | 1 | 166 |
| Total | 394 | 570 | 1468 | 1331 | 11 | 3774 |
Highest pathogenic variant AF is 0.00040516612
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000251.3 | 48 | MANE Select | |
| Ensembl | ENSP00000386331.3 | 48 | MANE Select | |
| RefSeq | NP_001120652.1 | 48 | Standard | |
| RefSeq | NP_001356294.1 | 47 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| myo7aa | Danio rerio | Structure: auditory receptor cell Quality: splayed abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Signaling by GPCR
- Signal Transduction
- The canonical retinoid cycle in rods (twilight vision)
- G alpha (i) signalling events
- Visual phototransduction
Biological Process
- phagolysosome assembly
- intracellular protein transport
- lysosome organization
- visual perception
- sensory perception of sound
Molecular Function
- microfilament motor activity
- protein binding
- calmodulin binding
- ATP binding
- protein domain specific binding
Cellular Component
- photoreceptor outer segment
- photoreceptor inner segment
- cytoplasm
- lysosomal membrane
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000409709
- Coding exons
- 48
- Length
- 86975
- Individuals with no LoFs
- 124977
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 199
- Defined
- 125176
- p
- 0.000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.07 | 1242 | 1.35e+3 | 0.918 | 0.0000884 | 14374 |
| Missense (PolyPhen) | 552 | 609.14 | 0.9062 | 6320 | ||
| Synonymous | -0.749 | 585 | 562 | 1.04 | 0.0000384 | 4197 |
| Loss of Function | 2.89 | 77 | 110 | 0.702 | 0.00000527 | 1285 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0010 | 0.00076 | notable |
| Latino/Admixed American | 0.00079 | 0.00078 | rare |
| Ashkenazi Jewish | 0.00080 | 0.00080 | rare |
| East Asian | 0.00045 | 0.00044 | rare |
| Finnish | 0.0013 | 0.0013 | notable |
| European (Non-Finnish) | 0.00073 | 0.00070 | rare |
| South Asian | 0.0011 | 0.0011 | notable |
| Other | 0.00084 | 0.00082 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Myosins are actin-based motor molecules with ATPase activity. Unconventional myosins serve in intracellular movements. Their highly divergent tails bind to membranous compartments, which are then moved relative to actin filaments. In the retina, plays an important role in the renewal of the outer photoreceptor disks. Plays an important role in the distribution and migration of retinal pigment epithelial (RPE) melanosomes and phagosomes, and in the regulation of opsin transport in retinal photoreceptors. In the inner ear, plays an important role in differentiation, morphogenesis and organization of cochlear hair cell bundles. Involved in hair-cell vesicle trafficking of aminoglycosides, which are known to induce ototoxicity (By similarity). Motor protein that is a part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A that mediates mechanotransduction in cochlear hair cells. Required for normal hearing. {ECO:0000250, ECO:0000269|PubMed:19643958, ECO:0000269|PubMed:21493626, ECO:0000269|PubMed:21687988, ECO:0000269|PubMed:21709241}.;
- Disease
- DISEASE: Usher syndrome 1B (USH1B) [MIM:276900]: USH is a genetically heterogeneous condition characterized by the association of retinitis pigmentosa with sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH1 is characterized by profound congenital sensorineural deafness, absent vestibular function and prepubertal onset of progressive retinitis pigmentosa leading to blindness. {ECO:0000269|PubMed:10094549, ECO:0000269|PubMed:10364543, ECO:0000269|PubMed:10447383, ECO:0000269|PubMed:10930322, ECO:0000269|PubMed:12112664, ECO:0000269|PubMed:15660226, ECO:0000269|PubMed:16679490, ECO:0000269|PubMed:23559863, ECO:0000269|PubMed:24831256, ECO:0000269|PubMed:25798947, ECO:0000269|PubMed:7870171, ECO:0000269|PubMed:8900236, ECO:0000269|PubMed:9002678, ECO:0000269|PubMed:9382091, ECO:0000269|PubMed:9718356}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal recessive, 2 (DFNB2) [MIM:600060]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:28281779, ECO:0000269|PubMed:9171832, ECO:0000269|PubMed:9171833}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal dominant, 11 (DFNA11) [MIM:601317]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA11 is characterized by onset after complete speech acquisition and subsequent gradual progression. {ECO:0000269|PubMed:15121790, ECO:0000269|PubMed:15221449, ECO:0000269|PubMed:15300860, ECO:0000269|PubMed:9354784}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.339
Intolerance Scores
- LoFtool
- 0.0260
- RVIS EVS
- -2.51
- RVIS percentile EVS
- 0.93
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.851
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | Medium | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |