OTOP1
protein-codingotopetrin 1
Gene summary
This gene encodes a transmembrane protein which belongs to the otopetrin domain protein family and is required for the formation of otoconia and otoliths, calcium carbonate biominerals within the inner ear of mammals that are required for the detection of linear acceleration and gravity. This gene modulates purinergic control of intracellular calcium in vestibular supporting cells. Naturally occurring mutations in the orthologous mouse gene are associated with nonsyndromic otoconia agenesis and a consequent balance defect. The orthologous mouse gene is also induced in white adipose tissue during obesity. The encoded protein is a component of a counterinflammatory pathway that attenuates obesity-induced adipose tissue inflammation and plays an adaptive role in maintaining metabolic homeostasis in obesity. [provided by RefSeq, Jul 2017]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~38.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to OTOP1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_177998.3. 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 | 1 | ||||
| missense | 110 | 5 | 115 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 111 | 5 | 0 | 116 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_819056.1 | 6 | MANE Select | |
| Ensembl | ENSP00000296358.4 | 6 | MANE Select |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| otop1 | Danio rerio | Structure: otolith Quality: quality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- detection of gravity
- biomineral tissue development
- cellular response to insulin stimulus
- inner ear morphogenesis
- negative regulation of interferon-gamma-mediated signaling pathway
Molecular Function
- proton channel activity
Cellular Component
- integral component of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000296358
- Coding exons
- 6
- Length
- 38087
- Individuals with no LoFs
- 125515
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 233
- Defined
- 125748
- p
- 0.000927
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.664 | 356 | 322 | 1.10 | 0.0000179 | 3874 |
| Missense (PolyPhen) | 117 | 106.19 | 1.1018 | 1369 | ||
| Synonymous | -0.312 | 141 | 136 | 1.03 | 0.00000804 | 1267 |
| Loss of Function | -1.95 | 30 | 20.5 | 1.47 | 0.00000103 | 244 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00043 | 0.00043 | rare |
| Latino/Admixed American | 0.00081 | 0.00081 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00044 | 0.00044 | rare |
| Finnish | 0.00055 | 0.00055 | rare |
| European (Non-Finnish) | 0.0013 | 0.0013 | notable |
| South Asian | 0.00092 | 0.00091 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Proton-selective channel that specifically transports protons into cells (PubMed:29371428). Proton channel activity is only weakly-sensitive to voltage (By similarity). Proton-selective channel activity is probably required in cell types that use changes in intracellular pH for cell signaling or to regulate biochemical or developmental processes (PubMed:29371428). In the vestibular system of the inner ear, required for the formation and function of otoconia, which are calcium carbonate crystals that sense gravity and acceleration (By similarity). Probably acts by maintaining the pH appropriate for formation of otoconia (By similarity). Regulates purinergic control of intracellular calcium in vestibular supporting cells (By similarity). May be involved in sour taste perception in sour taste cells by mediating entry of protons within the cytosol (By similarity). Also involved in energy metabolism, by reducing adipose tissue inflammation and protecting from obesity-induced metabolic dysfunction (By similarity). {ECO:0000250|UniProtKB:Q80VM9, ECO:0000269|PubMed:29371428}.;
Intolerance Scores
- LoFtool
- 0.927
- RVIS EVS
- 0.42
- RVIS percentile EVS
- 77.26
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.209
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |