UNC93B1
protein-codingunc-93 homolog B1, TLR signaling regulator
Gene summary
This gene encodes a protein that is involved in innate and adaptive immune response by regulating toll-like receptor signaling. The encoded protein traffics nucleotide sensing toll-like receptors to the endolysosome from the endoplasmic reticulum. Deficiency of the encoded protein has been associated with herpes simplex encephalitis. [provided by RefSeq, Feb 2014]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~13.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0024563
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0019751
Submitter: PanelApp Australia
Inheritance Pattern: SD
Disease ID:MONDO:0007915
Submitter: ClinGen
*UNC93B1* encodes an endoplasmic reticulum (ER) transmembrane protein involved in Toll-like receptor (TLR) trafficking from the ER to the endosomes. UNC93B1 recruits Syntenin-1 to its C-terminal end, where Syntenin-1 functions to inhibit TLR signaling. Variants in *UNC93B1* were first reported in relation to SLE in 2024 (PMIDs: 38207055, 38780621, 38831104, 38869500). Genetic evidence includes five missense variants and one in-frame insertion variant reported in six probands in four publications (PMIDs: 38207055, 38207015, 38780621, 38869500). Two and four of the variants were identified in a homozygous and heterozygous state, respectively, in the affected individuals. A case-control study using single-variant analysis for *UNC93B1* reported an odds ratio of 17.9 for developing SLE (PMID: 38831104). Experimental data includes evidence that *UNC93B1* variants reported in patients increase TLR7 signaling. Direct protein-protein interactions of UNC93B1 with TLR7 and Syntenin-1 were confirmed (PMIDs: 19451267, 31546246). Mouse models introducing *UNC93B1* variants known to cause upregulated TLR7 signaling resulted in multi-organ inflammation, glomerular disease, and positive autoantibodies (PMIDs: 38780621, 31546246, 38831104). In summary, there is **moderate** evidence supporting the relationship between variants of *UNC93B1* and a semidominant phenotype of Systemic Lupus Erythematosus. This classification was approved by the ClinGen Monogenic Systemic and Incomplete Lupus Erythematosus GCEP on the meeting date April 9, 2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0024563
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious
Intervention: Allergy/Immunology/Infectious
Rationale: Individuals may be susceptible to severe HSV infections, which can result in lethal sequlae or severe chronic impairment, and recognition may allow preventive measures as well as prompt treatment with anti-HSV medications (eg, acyclovir), which may improve outcome
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to UNC93B1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_030930.4. 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 | 5 | 144 | 6 | 155 | ||
| missense | 3 | 185 | 10 | 4 | 202 | |
| nonsense | 2 | 2 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 5 | 1 | 6 | 2 | 14 | |
| splice donor/acceptor (+/-2bp) | 4 | 2 | 6 | |||
| Total | 7 | 8 | 199 | 154 | 12 | 380 |
Highest pathogenic variant AF is 0.00004963323
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_112192.2 | 11 | MANE Select | |
| Ensembl | ENSP00000227471.3 | 11 | MANE Select | |
| Ensembl | ENSP00000434294.1 | 5 | Standard | |
| Ensembl | ENSP00000437195.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- miR-targeted genes in epithelium - TarBase
- miR-targeted genes in leukocytes - TarBase
- miR-targeted genes in lymphocytes - TarBase
- Trafficking and processing of endosomal TLR
- Toll-Like Receptors Cascades
Biological Process
- toll-like receptor signaling pathway
- adaptive immune response
- intracellular protein transport
- toll-like receptor 3 signaling pathway
- toll-like receptor 7 signaling pathway
Molecular Function
- protein transporter activity
- Toll-like receptor binding
Cellular Component
- Golgi membrane
- lysosome
- endosome
- endoplasmic reticulum
- endoplasmic reticulum membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000227471
- Coding exons
- 12
- Length
- 13878
- Individuals with no LoFs
- 3071
- Homozygous LoFs
- 121565
- Heterozygous LoFs
- 0
- Defined
- 124636
- p
- 0.843
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.86 | 234 | 329 | 0.711 | 0.0000205 | 3740 |
| Missense (PolyPhen) | 60 | 130.99 | 0.45803 | 1534 | ||
| Synonymous | 1.08 | 134 | 151 | 0.889 | 0.0000105 | 1203 |
| Loss of Function | 3.31 | 6 | 23.2 | 0.258 | 9.93e-7 | 294 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 1.0 | 0.93 | notable |
| Latino/Admixed American | 1.0 | 0.98 | notable |
| Ashkenazi Jewish | 1.0 | 0.94 | notable |
| East Asian | 1.0 | 0.97 | notable |
| Finnish | 1.0 | 0.50 | notable |
| European (Non-Finnish) | 1.0 | 0.93 | notable |
| South Asian | 1.0 | 0.99 | notable |
| Other | 1.0 | 0.90 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays an important role in innate and adaptive immunity by regulating nucleotide-sensing Toll-like receptor (TLR) signaling. Required for the transport of a subset of TLRs (including TLR3, TLR7 and TLR9) from the endoplasmic reticulum to endolysosomes where they can engage pathogen nucleotides and activate signaling cascades. May play a role in autoreactive B- cells removal. {ECO:0000269|PubMed:19006693}.;
- Disease
- DISEASE: Encephalopathy, acute, infection-induced, Herpes- specific, 1 (IIAE1) [MIM:610551]: A rare complication of human herpesvirus 1 (HHV-1) infection, occurring in only a small minority of HHV-1 infected individuals. It is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome. {ECO:0000269|PubMed:16973841}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Mutations in UNC93B1 resulting in autosomal recessive UNC93B1 deficieny predispose otherwise healthy individuals to isolated herpes simplex encephalitis due to impaired IFNs production. UNC93B1 deficieny, however, does not compromise immunity to most pathogens, unlike most known primary immunodeficiencies.;
Recessive Scores
- pRec
- 0.176
Essentials
- Essential (CRISPR2)
- S
- Indispensability pred.
- N
- Indispensability score
- 0.283
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |