TNFSF18

Chr 1

TNF superfamily member 18

Also known as: AITRL, GITRL, TL6, TNLG2A, hGITRL

NCBI Gene: 8995 ENSG00000120337 UniProt: Q9UNG2 OMIM: 603898

The protein encoded by TNFSF18 is a cytokine that binds to the TNFRSF18 receptor and regulates T-cell activation, proliferation, and survival, while also promoting leukocyte adhesion to endothelial cells. This gene is highly tolerant to loss-of-function variants based on population genetics data, and no Mendelian diseases have been definitively associated with TNFSF18 mutations to date. The gene's role in immune cell regulation suggests that if pathogenic variants were identified, they would likely affect immunological function.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This cytokine is a ligand for receptor TNFRSF18/AITR/GITR. It has been shown to modulate T lymphocyte survival in peripheral tissues. This cytokine is also found to be expressed in endothelial cells, and is thought to be important for interaction between T lymphocytes and endothelial cells. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.63

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.63LOEUF

pLI 0.000

Z-score 0.35

OE 0.86 (0.47–1.63)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.56Z-score

OE missense 1.16 (0.99–1.35)

115 obs / 99.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.86 (0.47–1.63)

0≤0.351.4

Missense OE?1.16 (0.99–1.35)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 6 / 7.0Missense obs/exp: 115 / 99.4Syn Z: 0.30

Background carrier burden — how many people carry a rare variant somewhere in TNFSF18?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 220

225 rare PASS variants

Rare truncating (LoF)

1 in 830

37 rare PASS variants

Rare synonymous (reference)

1 in 1,400

76 rare PASS variants

Rare missense and truncating variants are carried at similar rates in TNFSF18; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 240	1 in 3,500
South Asian	~43k	1 in 210	1 in 1,200
Remaining (unassigned)	~30k	1 in 160	1 in 6,000
European (Finnish)	~27k	1 in 760	none seen
Admixed American	~22k	1 in 160	1 in 2,300
African / African American	~21k	1 in 360	≈ 1 in 8,300
East Asian	~20k	1 in 130	1 in 2,500
Ashkenazi Jewish	~13k	1 in 1,500	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 210	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓