FAS

Gene Facts

• HGNC Symbol: FAS (HGNC:11920)
• HGNC Name: Fas cell surface death receptor
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: FAS1, APT1, TNFRSF6
• Alias symbols: CD95, APO-1
• %HI: 93.15
• pLI: 1
• LOEUF: 0.37
• Cytoband: 10q23.31
• Genomic Coordinates:

  GRCh37/hg19:	chr10:90750555-90776816
  GRCh38/hg38:	chr10:88964050-89017059

• MANE Select Transcript: NM_000043.6 ENST00000652046.1
• Function: Receptor for TNFSF6/FASLG. The adapter molecule FADD recruits caspase CASP8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. FAS-mediated apoptosis may have a role in the induction of peripheral tolerance, in the antigen- stimulated suicide of mature T-cells, or both. The secreted isoforms 2 to 6 block apoptosis (in ... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-35942
• ClinGen Curation ID: CCID:007125
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Little Evidence for Haploinsufficiency (1)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Assoc. with Reduced Penetrance: Yes
  Penetrance appears to be variable with ~77% of patients with heterozygous intracellular domain variants (ICD) but only 33% of those with heterozygous extracellular domains (ECD) exhibiting autoimmune lymphoproliferative syndrome (ALPS). However, ICD variants exert a dominant negative effect and inhibit apoptosis whilst patients with ECD variants (mostly LoF) retain sufficient protein from the wild type allele. LoF variants thus behave as a recessive variant and require a second hit - either rare homozygous germline LoF variants in consanguineous pedigrees or a second somatic hit such as by acquired uniparental disomy (UPD). Second hits are also found in non-FAS genes such as FASLG, FADD, Caspase-8 & Caspase-10.
• Last Evaluated: 02/08/2022

Haploinsufficiency (HI) Score Details

• HI Score: 1
• HI Evidence Strength: Little Evidence for Haploinsufficiency

HI Disease

• autoimmune lymphoproliferative syndrome

HI Evidence

• PUBMED: 21490157
  Kuehn et al (2011) sequenced the FAS gene in 108 ALPS probands and found 84 variants, which included nonsense and indels causing a frameshift. Using patient-derived transformed B-cell lines, the authors used flow cytometry to examine FAS cell surface expression. Mutant cell lines showed significantly reduced cell surface expression of FAS, in support of a haploinsufficient effect.
• PUBMED: 26563159
  de Bielke et al (2015) performed functional studies on 7 individuals diagnosed with ALPS who have the missense variant, C107Y. Two individuals had homozygous variants and severe disease, while the heterozygous carriers had a less severe phenotype. The authors found that the abnormal proteins were retained in the ER and not sent to the cell surface. These proteins were then degraded via transport to the proteasome and ubiquitination. A reduction in the amount of cell surface-expressed FAS results in ALPS, consistent with haploinsufficiency.
• PUBMED: 23524443
  Hauck et al (2013) a family with 12 members carrying a heterozygous germline start codon variant leading to FAS haploinsufficiency, 2 affected family members and the other ten variant-positive relatives were healthy. One of the affected family members was found to have somatic loss of heterozygosity, with no FAS expression. This evidence suggests that FAS haploinsufficiency alone does not cause ALPS-FAS, but that modifying genetic events are crucial for its pathogenesis.
• PUBMED: 34171534
  Magerus et al (2021) reviewed the literature and a cohort of 165 French patients; ALPS can be caused by germline (ALPS-FAS), somatic (ALPS-sFAS) or a combination of both (ALPS-FAS/sFAS) variants of FAS. Homozygous FAS variants result in a severe and early phenotype requiring BMT. Penetrance appears to be variable with ~77% of patients with heterozygous intracellular domain variants (ICD) but only 33% of the those with heterozygous extracellular domains (ECD) having phenotype. However, the ICD variants exert a dominant negative effect and inhibit apoptosis whilst patients with ECD variants (mostly LoF) retain sufficient protein from the wild type allele. LoF variants thus behave as a recessive variant and require a second hit - either rare homozygous germline LoF variants in consanguineous pedigrees or a second somatic hit such as by acquired UPD. Second hits are also found in non-FAS genes such as FASLG, FADD, Caspase-8 & Caspase-10.

• HI Evidence Comments: Haploinsufficiency results in a risk for autoimmune lymphoproliferative syndrome, with incomplete penetrance. Germline haploinsufficiency variants, followed by a second somatic variant, will result in in ALPS. Most ALPS cases are due to missense variants in the death domain of the FAS (or CD95) protein, which results in a dominant-negative effect on the WT protein. This form of the disease is highly penetrant. Other missense variants and small deletions resulting in haploinsufficiency are less penetrant. Some ALPS cases are caused by variants in the extracellular domain of the protein, resulting in a reduced level of gene product localizing to the cell surface. This alternate form of ALPS is less penetrant. In addition, biallelic germline variants result in severe disease.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity