UNC13D
protein-codingunc-13 homolog D, the group of UNC13 homologs
Gene summary
This gene encodes a protein that is a member of the UNC13 family, containing similar domain structure as other family members but lacking an N-terminal phorbol ester-binding C1 domain present in other Munc13 proteins. The protein appears to play a role in vesicle maturation during exocytosis and is involved in regulation of cytolytic granules secretion. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis type 3, a genetically heterogeneous, rare autosomal recessive disorder. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~17.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0012146
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AR
Disease ID:MONDO:0012146
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0015541
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012146
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0012146
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0012146
Submitter: ClinGen
*UNC13D* was first reported in relation to autosomal recessive familial hemophagocytic lymphohistiocytosis 3 (FHL3) in 2003 (Feldmann J et al., PMID: 14622600). FHL3 is a heterogeneous disease characterized by fever, hepatosplenomegaly, and hemophagocytosis with frequent occurrence of a range of additional features, including splenomegaly, central nervous system involvement (e.g., headache, encephalopathy, cranial nerve palsies, seizures, and ataxia), viral infections, malignancy (e.g., leukemia), neutropenia, thrombocytopenia, and deficient natural killer cell activity (PMID: 14622600, 31506890, 32107531, 32679608, 34964741). Furthering the phenotypic spectrum, individuals with late-onset HLH and/or atypical features have been reported, which may be associated with hypomorphic variants in *UNC13D* (PMID: 17993578, 21881043, 28848550, 29312353). Eight variants (in-frame deletion, nonsense, frameshift, canonical splice site, intronic) that have been reported in six probands in two publications (PMIDs: 14622600, 34964741) are included in this curation. Notably, more than 300 patients with FHL associated with *UNC13D* variants have been reported to date (PMID: 32679608). However, the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of disease is known to be loss of function. Among variants identified in FHL3 patients, an 253-kb inversion and deep intronic variants have been reported in many cases (PMID: 21931115, 24470399). Interestingly, there is also evidence supporting an additional digenic mode of inheritance of FHL, where heterozygous *UNC13D* variants have been identified with heterozygous variants in other degranulation pathway genes in patients with FHL (PMID: 34868048). This gene-disease association is also supported by experimental evidence, including animal models, expression studies, in vitro functional assays, and gene transfer rescue studies (PMIDs: 14522600, 1554890, 17420270, 20823128, 23590328, 24842371, 31032638). *UNC13D*, encoding Munc13-4, has been determined to be a positive regulator of degranulation (PMID: 15548590). Patient cells demonstrate defects in natural killer cell and CD8 T cell degranulation (PMID: 20823128), which can be rescued by retroviral transduction of *UNC13D* (PMID: 31032638). A mouse model of FHL3 (i.e., Jinx) recapitulates aspects of human disease and transfection of UNC13D into Jinx-derived cells rescues some of these defects (PMID: 17420270, 23590328). In summary, *UNC13D* is definitively associated with autosomal recessive familial hemophagocytic lymphohistiocytosis 3. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Hematologic; Oncologic
Intervention: Allergy/Immunology/Infectious; Hematologic; Oncologic
Rationale: Early recognition may allow prompt treatment, as individuals frequently have fatal outcomes unless treated by control of infectious triggers and chemoimmunotherapy, which can be beneficial; HSCT has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to UNC13D variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_199242.3. 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 | 8 | 440 | 2 | 450 | ||
| missense | 3 | 11 | 526 | 27 | 4 | 571 |
| nonsense | 35 | 15 | 3 | 53 | ||
| start loss | 0 | |||||
| frameshift | 62 | 16 | 2 | 80 | ||
| splice donor/acceptor (+/-2bp) | 13 | 37 | 7 | 57 | ||
| Total | 113 | 79 | 546 | 467 | 6 | 1211 |
Highest pathogenic variant AF is 0.00035217556
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_954712.1 | 32 | MANE Select | |
| Ensembl | ENSP00000207549.3 | 32 | MANE Select | |
| Ensembl | ENSP00000388093.1 | 33 | Standard | |
| Ensembl | ENSP00000388093.1 | 33 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Deregulation of Rab and Rab Effector Genes in Bladder Cancer
- Neutrophil degranulation
- Innate Immune System
- Immune System
Biological Process
- granuloma formation
- germinal center formation
- phagocytosis
- regulation of mast cell degranulation
- neutrophil degranulation
Molecular Function
- protein binding
- Rab GTPase binding
Cellular Component
- extracellular region
- lysosome
- late endosome
- cytosol
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000207549
- Coding exons
- 32
- Length
- 17493
- Individuals with no LoFs
- 125591
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 157
- Defined
- 125748
- p
- 0.000624
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.241 | 662 | 645 | 1.03 | 0.0000434 | 6963 |
| Missense (PolyPhen) | 213 | 201.87 | 1.0551 | 2318 | ||
| Synonymous | 0.503 | 273 | 284 | 0.962 | 0.0000196 | 2212 |
| Loss of Function | 3.09 | 40 | 67.3 | 0.594 | 0.00000357 | 693 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00019 | 0.00018 | rare |
| Latino/Admixed American | 0.00044 | 0.00043 | rare |
| Ashkenazi Jewish | 0.00020 | 0.00020 | rare |
| East Asian | 0.00044 | 0.00044 | rare |
| Finnish | 0.00024 | 0.00018 | rare |
| European (Non-Finnish) | 0.0010 | 0.00095 | notable |
| South Asian | 0.00046 | 0.00046 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays a role in cytotoxic granule exocytosis in lymphocytes. Required for both granule maturation and granule docking and priming at the immunologic synapse. Regulates assembly of recycling and late endosomal structures, leading to the formation of an endosomal exocytic compartment that fuses with perforin-containing granules at the immunologic synapse and licences them for exocytosis. Regulates Ca(2+)-dependent secretory lysosome exocytosis in mast cells. {ECO:0000269|PubMed:15548590, ECO:0000269|PubMed:17237785}.;
- Disease
- DISEASE: Familial hemophagocytic lymphohistiocytosis 3 (FHL3) [MIM:608898]: A rare disorder characterized by immune dysregulation with hypercytokinemia, defective function of natural killer cell, and massive infiltration of several organs by activated lymphocytes and macrophages. The clinical features of the disease include fever, hepatosplenomegaly, cytopenia, and less frequently neurological abnormalities ranging from irritability and hypotonia to seizures, cranial nerve deficits and ataxia. {ECO:0000269|PubMed:14622600}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.160
Intolerance Scores
- LoFtool
- 0.763
- RVIS EVS
- 0.08
- RVIS percentile EVS
- 59.44
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.823
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |