• 30
    Haplo
    Score
  • 30
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
FASLG (HGNC:11936) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
Fas ligand
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
APT1LG1, TNFSF6
Alias symbols
FasL, CD178
%HI
7.98(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.18(Read more about gnomAD pLI score)
LOEUF
0.72(Read more about gnomAD LOEUF score)
Cytoband
1q24.3
Genomic Coordinates
GRCh37/hg19: chr1:172628243-172636016 NCBI Ensembl UCSC
GRCh38/hg38: chr1:172659103-172666876 NCBI Ensembl UCSC
MANE Select Transcript
NM_000639.3 ENST00000367721.3 (Read more about MANE Select)
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... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-3940
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Gene Associated with Autosomal Recessive Phenotype (30)
Triplosensitivity:
Gene Associated with Autosomal Recessive Phenotype (30)
Assoc. with Reduced Penetrance:
Uncertain
Last Evaluated:
10/11/2023

Haploinsufficiency (HI) Score Details

HI Score:
30
HI Evidence Strength:
Gene Associated with Autosomal Recessive Phenotype (Disclaimer)
HI Disease:
  • autoimmune lymphoproliferative syndrome type 1 Monarch
HI Evidence Comments:
Variants in FASLG have been reported in individuals with autoimmune lymphoproliferative syndrome, or ALPS. Individuals have been reported with ALPS or ALPS-like features. Several early case studies suggested that FASLG-related ALPS is most often transmitted in an autosomal dominant manner, and the proposed disease mechanism for this association can be haploinsufficiency or dominant negative; however, the evidence supporting the dominant inheritance is not strong. Two study groups (Sneller 1992, PMID: 1386609; Fisher 1995, PMID: 7540117) identified heterozygous mutations in the FASLG gene in five unrelated patients with ALPS1A. These variants included a frameshift variant, two splice variants, one nonsense variant, and one missense variant. The studies suggested that the frameshift variant appeared to cause a simple loss of function; however, four others had a dominant negative phenotype when co-expressed with normal FAS. These variants were identified through Sanger sequencing, and no second allele was detected in all the patients. Family studies demonstrated these variants were inherited from one of their unaffected parents. These variants were not reported in HGMD. Another study reported a heterozygous variant in 4 patients, including two nonsense variants, p.K230* in patient 1 and p.R234* in patient 4, and a missense variant, p.D244Y, in patient 3, which was inherited from a father who was reported to have regression of lymphadenopathy. The mutation in patient 1 was absent in her mother and son, and the inheritance of this variant could not be determined, but no other family members were affected. The p.R234* variant in patient 4 was also presented in unaffected mother and sister [Drappa 1996, PMID: 17605793]. One case that supports AD inheritance was about an ALPS patient who harbored a heterozygous c.530A>G (p.R156G) mutation, whose father and paternal grandmother share a heterozygous variant but neither of them had full picture of ALPS. The study also mentioned that this variant produced a dominant-interfering FasL protein that bound to the wild-type FasL protein and prevented it from effectively inducing apoptosis [Bi 2007, PMID: 17605793]. However, this variant is common in gnomAD with a MAF of 0.015% (10/68040) in NFE. The REVEL score is 0.284. However, more ALPS patients with homozygous variants have been described, and most were from consanguineous families [Del-Rey 2006, PMID: 16627752; Van der Burg 2000, PMID: 10709732; Nabhani 2014, PMID: 25451160; RuiZ-Garcia 2015, PMID: 26334989; Sobh 2016, PMID: 26456038; AI-Herz 2019, PMID: 30697212; Magerus-Chatinet 2012, PMID: 22857793]. The reported variants include both missense variants and truncating variants. Their heterozygous parents and siblings were reported to be healthy without the related clinical features, further supporting the autosomal recessive inheritance of this disease. In addition, ALPS due to heterozygous germline variants and additional somatic mutations in the FASLG gene have also been reported. Heterozygous carriers without a second somatic hit were unaffected [Magerus-Chatinet 2011, PMID: 21183795; Holzelova 2004, PMID: 15459302; Dowdell 2010, PMID: 20360470]. Reported variants also included truncating variants. Patients with somatic FAS mutations were clinically similar to those with germline FAS mutations, although they had a slightly lower incidence of splenectomy and lower lymphocyte counts. Several studies also pointed out that the recessive lymphoproliferation (lpr) phenotype and the generalized lymphoproliferative disease (gld) phenotype are mouse models of aberrant T-cell accumulation.

Triplosensitivity (TS) Score Details

TS Score:
30
TS Evidence Strength:
Gene Associated with Autosomal Recessive Phenotype (Disclaimer)

Genomic View

Select assembly: (NC_000001.10) (NC_000001.11)