STX11
protein-codingsyntaxin 11, the group of Syntaxins
Gene summary
This gene encodes a member of the syntaxin family. Syntaxins have been implicated in the targeting and fusion of intracellular transport vesicles. This family member may regulate protein transport among late endosomes and the trans-Golgi network. Mutations in this gene have been associated with familial hemophagocytic lymphohistiocytosis. [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 ~41.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0015541
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011336
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0011336
Submitter: ClinGen
STX11 was first reported in relation to autosomal recessive familial hemophagocytic lymphohistiocytosis 4 (FHL4) in 2005 (zur Stadt U et al., 2005, PMID: 15703195). FHL is characterized by episodes of severe and overwhelming systemic immune activation which is often lethal in the absence of appropriate treatment and subsequent allogeneic hematopoietic cell transplantation (HCT). Typical features include fever, splenomegaly, cytopenias, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, elevated levels of soluble IL-2 receptor, decreased or absent NK cell function, and hemophagocytosis observed on pathologic inspection of bone marrow or other tissues. Patients with defects in syntaxin 11 result in severely compromised NK degranulation and cytotoxicity. STX11 is expressed in many tissues, but with regard to the immune system, Syntaxin 11 is necessary for normal NK cell and CD8+T cell cytotoxic granule exocytosis and has been implicated in being involved in neutrophil granule exocytosis as well. The exact molecular mechanism of STX11 is not clear. This curation includes 11 variants (including in-frame deletions, missense, nonsense, and frameshift) found in 10 probands from two publications (PMIDs: 20486178, 16582076, 24459464, 26709266, 21298754, 19967551, 31207086 and 31770233). Additional cases are available in the literature however the maximum score for genetic evidence has been reached. A role in disease is supported by increased expression of STX11 in NK cells and CD8+ T cells, as well as in NK92 cells (PMID:17525286). Functional alteration in the patient's cells also showed how a mutation resulted in a complete loss of STX11 function (PMID: 20486178). A Stx11−/− mouse model demonstrated the phenotypes associated with FHL4 and exhibited a defective degranulation and cytotoxic activity of lymphocytes in vitro, confirming the critical role of this SNARE protein in cytotoxic granule exocytosis. Recuse of the phenotype was also seen in this same mouse model (PMID:23160464). In summary, STX11 is definitively associated with autosomal recessive FHL4. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0011336
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Neurologic; Oncologic
Intervention: Allergy/Immunology/Infectious; Oncologic
Rationale: Antibiotics or antiviral agents can be beneficial to treat/prevent infections that can trigger an exaggerated inflammatory response. Chemo/immunotherapy can be beneficial; HSCT has been described
Comments: Some individuals have been described as having remission without treatment; It has been suggested that variants may also confer risk for other malignancies.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to STX11 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003764.4. 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 | 141 | 141 | ||||
| missense | 1 | 138 | 10 | 1 | 150 | |
| nonsense | 6 | 6 | 12 | |||
| start loss | 0 | |||||
| frameshift | 6 | 11 | 17 | |||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 13 | 17 | 138 | 151 | 1 | 320 |
Highest pathogenic variant AF is 0.000010963815
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003755.2 | 1 | MANE Select | |
| Ensembl | ENSP00000356540.4 | 1 | MANE Select | |
| Ensembl | ENSP00000513678.1 | 1 | Standard | |
| Ensembl | ENSP00000513678.1 | 1 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- SNARE interactions in vesicular transport - Homo sapiens (human)
- Nicotine Pathway (Dopaminergic Neuron), Pharmacodynamics
Biological Process
- intracellular protein transport
- exocytosis
- vesicle fusion
- synaptic vesicle fusion to presynaptic active zone membrane
- vesicle docking
Molecular Function
- SNARE binding
- SNAP receptor activity
- protein binding
Cellular Component
- Golgi apparatus
- plasma membrane
- synaptic vesicle
- endomembrane system
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000367568
- Coding exons
- 1
- Length
- 37845
- Individuals with no LoFs
- 125723
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 21
- Defined
- 125744
- p
- 0.0000835
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.131 | 211 | 206 | 1.03 | 0.0000177 | 1884 |
| Missense (PolyPhen) | 71 | 78.502 | 0.90444 | 658 | ||
| Synonymous | 0.150 | 96 | 97.9 | 0.981 | 0.00000968 | 559 |
| Loss of Function | 0.806 | 6 | 8.54 | 0.702 | 4.64e-7 | 87 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00043 | 0.00043 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: SNARE that acts to regulate protein transport between late endosomes and the trans-Golgi network.;
- Disease
- DISEASE: Familial hemophagocytic lymphohistiocytosis 4 (FHL4) [MIM:603552]: 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:15703195}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.183
Intolerance Scores
- LoFtool
- 0.438
- RVIS EVS
- 0.64
- RVIS percentile EVS
- 83.98
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.539
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |