FASLG
protein-codingFas ligand, the group of CD molecules|Tumor necrosis factor superfamily|Death inducing signaling complex
Gene summary
This gene is a member of the tumor necrosis factor superfamily. The primary function of the encoded transmembrane protein is the induction of apoptosis triggered by binding to FAS. The FAS/FASLG signaling pathway is essential for immune system regulation, including activation-induced cell death (AICD) of T cells and cytotoxic T lymphocyte induced cell death. It has also been implicated in the progression of several cancers. Defects in this gene may be related to some cases of systemic lupus erythematosus (SLE). Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2014]
- APT1LG1
- TNFSF6
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~7.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0017979
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0017979
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0011158
Submitter: ClinGen
*FASLG *(i.e., FAS ligand) was originally reported in relation to autosomal dominant autoimmune lymphoproliferative sydrome (ALPS) by by Wu et al. in 1996 (PMID: 8787672). Autoimmune lymphoproliferative syndrome is a disease characterized by signs of lymphoproliferation including lymphadenopathy and splenomegaly, as well as features of autoimmunity, often including combs positive hemolytic anemia. Biomarkers of the disease include increased IgG, increased Il-10, increased serum B12, and a very notable increase in the number of double negative T cells. There is a significantly elevated risk for Hodgkin lymphoma and there is an additional risk for other autoimmune diseases such as glomerulonephritis or autoimmune hepatitis. Similar to *FAS* variants, which are the most common cause of ALPS, it was originally thought that heterozygous *FASLG* variants were associated with ALPS. However, previously characterized patients with heterozygous variants did not display double negative T cells or other biomarkers characteristic of the disease (PMID: 8787672 and PMID: 17605793). Additionally, an in depth review from Maccari et al., PMID: 36621650, found that disease carriers had normal FasL-mediated cytotoxicity in patient T cells. More than 7 homozygous variants (missense and frameshift) in 7 probands have been reported to cause ALPS due to *FASLG* deficiency to date (PMID: 25451160, 22857792, 26334989, 16627752, 26456038, 36621650). The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by animal models, the biochemical function of FAS/FASL signaling, and cell culture models. From Karray S, et al., (PMID: 14764677) FASL (-/-) mice recapitulate several key features of patients with bi-allelic FASLG loss of function variants. Notably, FASLG knock out mice and probands both demonstrated phenotypes such as lymphadenopathy, hepatosplenomegaly, a greatly increased percentage of double negative T cells, increased Igg, and failure to thrive. Further experimental evidence comes from the well characterized role of FAS/FASL signaling in CD8 cytotoxic T cell function and activation induced cell death, which through apoptosis limits the number of clonal T cells after antigen elimination and importantly eliminates autoreactive T cells that have evaded self-reactivity screening in the thymus by negative selection. Failure of the FAS/FASLG pathway results lymphoproliferation and autoimmunity due to defective signaling that fails to eliminate auto-reactive T cells and fails to curve the immune response after antigen elimination. Finally, experimental evidence is supported by FASL deficient lymphocytes which display defective cytotoxic activity and impaired FAS/FASL signaling Lowin B, et al., PMID: 7520535. In summary, there is definitive evidence supporting the relationship between *FASLG* and autosomal recessive autoimmune lyphoproliferative syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0011158
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0011158
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011158
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0011158
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Hematologic; Oncologic; Renal
Intervention: Allergy/Immunology/Infectious; Oncologic
Rationale: Lymphoproliferation can be suppressed with medications such as corticosteroids, cyclosporine, tacrolimus, sirolimus, and mycophenolate mofetil; BMT/HSCT the only curative treatment for ALPS, has to date mostly been reported in patients with severe clinical findings; Surveillance for manifestations of lymphoproliferation and autoimmunity, and specialized imaging studies to detect malignant transformation may be beneficial
Comments: Biallelic variants have been described as resulting in more severe presentations, including as relates to autoimmunity and lymphoproliferation
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FASLG variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000639.3. 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 | 64 | 65 | |||
| missense | 1 | 1 | 82 | 14 | 98 | |
| nonsense | 1 | 1 | 2 | |||
| start loss | 0 | |||||
| frameshift | 1 | 1 | 2 | 4 | ||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 3 | 3 | 85 | 78 | 0 | 169 |
Highest pathogenic variant AF is 0.0000018591669
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000630.1 | 4 | MANE Select | |
| Ensembl | ENSP00000356694.2 | 4 | MANE Select | |
| RefSeq | NP_001289675.1 | 2 | Standard | |
| Ensembl | ENSP00000344739.3 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| faslg | Danio rerio | Structure: post-vent region Quality: increased curvature abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- Type I diabetes mellitus - Homo sapiens (human)
- Neurotrophin signaling pathway - Homo sapiens (human)
- Allograft rejection - Homo sapiens (human)
- Graft-versus-host disease - Homo sapiens (human)
Biological Process
- negative regulation of transcription by RNA polymerase II
- apoptotic process
- activation of cysteine-type endopeptidase activity involved in apoptotic process
- inflammatory cell apoptotic process
- immune response
Molecular Function
- signaling receptor binding
- death receptor binding
- cytokine activity
- tumor necrosis factor receptor binding
- protein binding
Cellular Component
- extracellular region
- extracellular space
- nucleus
- plasma membrane
- integral component of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000367721
- Coding exons
- 4
- Length
- 7861
- Individuals with no LoFs
- 125744
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 125748
- p
- 0.0000159
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.575 | 135 | 155 | 0.870 | 0.00000788 | 1819 |
| Missense (PolyPhen) | 26 | 42.668 | 0.60935 | 492 | ||
| Synonymous | -0.250 | 66 | 63.5 | 1.04 | 0.00000342 | 575 |
| Loss of Function | 2.20 | 3 | 10.8 | 0.277 | 5.43e-7 | 127 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Cytokine that binds to TNFRSF6/FAS, a receptor that transduces the apoptotic signal into cells (PubMed:26334989, PubMed:9228058). Involved in cytotoxic T-cell-mediated apoptosis, natural killer cell-mediated apoptosis and in T-cell development (PubMed:9228058, PubMed:7528780, PubMed:9427603). Initiates fratricidal/suicidal activation-induced cell death (AICD) in antigen-activated T-cells contributing to the termination of immune responses (By similarity). TNFRSF6/FAS-mediated apoptosis has also a role in the induction of peripheral tolerance (By similarity). Binds to TNFRSF6B/DcR3, a decoy receptor that blocks apoptosis (PubMed:27806260). {ECO:0000250|UniProtKB:P41047, ECO:0000269|PubMed:17557115, ECO:0000269|PubMed:27806260, ECO:0000269|PubMed:7528780, ECO:0000269|PubMed:9228058, ECO:0000269|PubMed:9427603}.; FUNCTION: FasL intracellular domain: Cytoplasmic form induces gene transcription inhibition. {ECO:0000269|PubMed:17557115}.;
- Disease
- DISEASE: Autoimmune lymphoproliferative syndrome 1B (ALPS1B) [MIM:601859]: A disorder of apoptosis that manifests in early childhood and results in the accumulation of autoreactive lymphocytes. It is characterized by non-malignant lymphadenopathy with hepatosplenomegaly, and autoimmune hemolytic anemia, thrombocytopenia and neutropenia. {ECO:0000269|PubMed:26334989, ECO:0000269|PubMed:8787672}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.848
Intolerance Scores
- LoFtool
- 0.0714
- RVIS EVS
- -0.41
- RVIS percentile EVS
- 26.23
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.723
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |