TIGIT

Chr 3

T cell immunoreceptor with Ig and ITIM domains

Also known as: VSIG9, VSTM3, WUCAM

NCBI Gene: 201633 ENSG00000181847 UniProt: Q495A1 OMIM: 612859

TIGIT encodes an inhibitory immune receptor that suppresses T-cell and NK cell activation by binding to ligands PVR/CD155 and NECTIN2/CD112 on antigen-presenting cells, thereby modulating immune responses through inhibition of PI3K, MAPK, and NF-kappa-B signaling pathways. The gene shows low constraint to loss-of-function variation (pLI 0.02, LOEUF 1.05), and no Mendelian diseases have been established from mutations in this gene. TIGIT is primarily studied in the context of cancer immunotherapy and autoimmune diseases rather than pediatric neurogenetic disorders.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the PVR (poliovirus receptor) family of immunoglobin proteins. The product of this gene is expressed on several classes of T cells including follicular B helper T cells (TFH). The protein has been shown to bind PVR with high affinity; this binding is thought to assist interactions between TFH and dendritic cells to regulate T cell dependent B cell responses.[provided by RefSeq, Sep 2009]

OMIM ResearchGenerating clinical summary…

Active trials

795

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.05

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.05LOEUF

pLI 0.018

Z-score 1.48

OE 0.46 (0.23–1.05)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.04Z-score

OE missense 1.01 (0.88–1.16)

143 obs / 141.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.46 (0.23–1.05)

0≤0.351.4

Missense OE?1.01 (0.88–1.16)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 4 / 8.7Missense obs/exp: 143 / 141.6Syn Z: 0.61

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

388 rare PASS variants

Rare truncating (LoF)

1 in 2,800

48 rare PASS variants

Rare synonymous (reference)

1 in 400

159 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TIGIT. 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 150	1 in 6,700
South Asian	~43k	1 in 120	1 in 870
Remaining (unassigned)	~30k	1 in 120	1 in 1,500
European (Finnish)	~27k	1 in 530	none seen
Admixed American	~22k	1 in 140	1 in 1,200
African / African American	~21k	1 in 150	1 in 740
East Asian	~20k	1 in 160	1 in 1,700
Ashkenazi Jewish	~13k	1 in 670	none seen
Middle Eastern	~2,884	1 in 200	≈ 1 in 720

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 4 coding exons well covered in gnomAD exomes and genomes.? see exons ↓