TNFAIP3

Chr 6AD

TNF alpha induced protein 3

Also known as: A20, AIFBL1, AISBL, OTUD7C, TNFA1P2

NCBI Gene: 7128 ENSG00000118503 UniProt: P21580 OMIM: 191163

This gene encodes a ubiquitin-editing enzyme that terminates NF-kappa-B inflammatory signaling pathways by deubiquitinating key proteins like RIPK1, TRAF6, and MALT1 in response to cytokines such as TNF and IL-1 beta. Mutations cause autoinflammatory syndrome, familial, Behcet-like 1, which follows an autosomal dominant inheritance pattern. The protein functions as an essential component in controlling immune and inflammatory responses by ensuring these signaling pathways remain transient rather than sustained.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene was identified as a gene whose expression is rapidly induced by the tumor necrosis factor (TNF). The protein encoded by this gene is a zinc finger protein and ubiqitin-editing enzyme, and has been shown to inhibit NF-kappa B activation as well as TNF-mediated apoptosis. The encoded protein, which has both ubiquitin ligase and deubiquitinase activities, is involved in the cytokine-mediated immune and inflammatory responses. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2012]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.201 OMIM phenotype

Clinical Summary— TNFAIP3

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

5 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.20LOEUF

pLI 1.000

Z-score 4.93

OE 0.06 (0.02–0.20)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.45Z-score

OE missense 0.81 (0.75–0.88)

387 obs / 476.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.20)

0≤0.351.4

Missense OE?0.81 (0.75–0.88)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 2 / 32.2Missense obs/exp: 387 / 476.2Syn Z: 1.55

This gene — mechanism propensity

0.2898th %ile

GOF

0.3887th %ile

LOF

0.72top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · LOEUF 0.20

Literature Evidence

LOFIn addition, 1 of 24 patients with a 6q deletion had an inactivating somatic mutation in TNFAIP3, another negative regulator of NF-kappa-B. Monoallelic deletions of chromosome 6q23, including the TNFAIP3 gene, were identified in 38% of patients, suggesting that haploinsufficiency can predispose to t1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References