TNFAIP3

TNF alpha induced protein 3, the group of OTU domain containing

Basic information

Region (hg38): 6:137867214-137883314

Links

ENSG00000118503 ∙ NCBI:7128 ∙ OMIM:191163 ∙ HGNC:11896 ∙ Uniprot:P21580 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autoinflammatory syndrome, familial, Behcet-like 1 (Strong), mode of inheritance: AD
• hereditary pediatric Behçet-like disease (Supportive), mode of inheritance: AD
• hereditary pediatric Behçet-like disease (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Autoinflammatory syndrome, familial, Behcet-like 1	AD	Allergy/Immunology/Infectious	Individuals have been described with a multisystem autoinflammatory syndrome, and medical treatment (with TNF inhibitors or colchicine) has been described as beneficial	Allergy/Immunology/Infectious	26642243

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TNFAIP3 gene.

• not provided (35 variants)
• Autoinflammatory syndrome, familial, Behcet-like 1 (4 variants)
• Autoinflammatory syndrome, familial, Behcet-like (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TNFAIP3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	105	4	111
missense	1		239	23	9	272
nonsense	14	8	2			24
start loss						0
frameshift	22	2	6			30
inframe indel			3			3
splice donor/acceptor (+/-2bp)		1				1
splice region			11	6	2	19
non coding			1	31	8	40
Total	37	11	253	159	21

Variants in TNFAIP3

This is a list of pathogenic ClinVar variants found in the TNFAIP3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
6-137871243-C-A			Uncertain significance (Jul 26, 2022)
6-137871249-C-T		Autoinflammatory syndrome, familial, Behcet-like	Likely pathogenic (Dec 26, 2019)
6-137871250-A-G			Uncertain significance (Feb 01, 2019)
6-137871261-T-C			Likely benign (Jun 13, 2021)
6-137871263-G-A			Likely benign (Aug 09, 2022)
6-137871264-A-G		Inborn genetic diseases	Uncertain significance (Oct 05, 2023)
6-137871273-C-T			Uncertain significance (Aug 12, 2022)
6-137871287-G-C			Uncertain significance (May 03, 2023)
6-137871289-T-C		Inborn genetic diseases	Uncertain significance (Dec 30, 2023)
6-137871290-A-T			Likely benign (Dec 29, 2022)
6-137871292-G-A			Uncertain significance (Oct 21, 2021)
6-137871301-C-T			Uncertain significance (Dec 21, 2021)
6-137871312-AT-A			Pathogenic (Jan 02, 2024)
6-137871314-T-A			Likely benign (Mar 04, 2023)
6-137871315-T-C			Uncertain significance (Feb 01, 2022)
6-137871329-TG-T			Pathogenic (Aug 01, 2022)
6-137871333-A-C			Uncertain significance (Mar 22, 2023)
6-137871340-A-G		Autoinflammatory syndrome, familial, Behcet-like 1	Uncertain significance (Jun 01, 2022)
6-137871343-AT-A			Pathogenic (Feb 08, 2021)
6-137871352-C-G			Benign (Jan 15, 2023)
6-137871360-C-T			Pathogenic (Nov 03, 2022)
6-137871361-G-A			Uncertain significance (Nov 08, 2023)
6-137871368-A-C			Likely benign (Oct 24, 2023)
6-137871368-A-G			Likely benign (Mar 08, 2021)
6-137871382-G-C		Inborn genetic diseases	Uncertain significance (Dec 13, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TNFAIP3	protein_coding	protein_coding	ENST00000237289	8	16099

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000284	125742	0	4	125746	0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.45	387	476	0.813	0.0000282	5249
Missense in Polyphen		107	189.73	0.56395		2191
Synonymous	1.55	157	184	0.854	0.0000118	1498
Loss of Function	4.93	2	32.2	0.0621	0.00000174	373

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000579	0.0000579
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000925	0.0000462
European (Non-Finnish)	0.00000889	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Ubiquitin-editing enzyme that contains both ubiquitin ligase and deubiquitinase activities. Involved in immune and inflammatory responses signaled by cytokines, such as TNF-alpha and IL-1 beta, or pathogens via Toll-like receptors (TLRs) through terminating NF-kappa-B activity. Essential component of a ubiquitin-editing protein complex, comprising also RNF11, ITCH and TAX1BP1, that ensures the transient nature of inflammatory signaling pathways. In cooperation with TAX1BP1 promotes disassembly of E2-E3 ubiquitin protein ligase complexes in IL-1R and TNFR-1 pathways; affected are at least E3 ligases TRAF6, TRAF2 and BIRC2, and E2 ubiquitin-conjugating enzymes UBE2N and UBE2D3. In cooperation with TAX1BP1 promotes ubiquitination of UBE2N and proteasomal degradation of UBE2N and UBE2D3. Upon TNF stimulation, deubiquitinates 'Lys-63'-polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains. This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NF-kappa-B. Deubiquitinates TRAF6 probably acting on 'Lys-63'-linked polyubiquitin. Upon T-cell receptor (TCR)-mediated T-cell activation, deubiquitinates 'Lys-63'-polyubiquitin chains on MALT1 thereby mediating disassociation of the CBM (CARD11:BCL10:MALT1) and IKK complexes and preventing sustained IKK activation. Deubiquitinates NEMO/IKBKG; the function is facilitated by TNIP1 and leads to inhibition of NF-kappa-B activation. Upon stimulation by bacterial peptidoglycans, probably deubiquitinates RIPK2. Can also inhibit I-kappa-B-kinase (IKK) through a non-catalytic mechanism which involves polyubiquitin; polyubiquitin promotes association with IKBKG and prevents IKK MAP3K7-mediated phosphorylation. Targets TRAF2 for lysosomal degradation. In vitro able to deubiquitinate 'Lys-11'-, 'Lys-48'- and 'Lys-63' polyubiquitin chains. Inhibitor of programmed cell death. Has a role in the function of the lymphoid system. Required for LPS- induced production of proinflammatory cytokines and IFN beta in LPS-tolerized macrophages. {ECO:0000269|PubMed:14748687, ECO:0000269|PubMed:15258597, ECO:0000269|PubMed:16684768, ECO:0000269|PubMed:17961127, ECO:0000269|PubMed:18164316, ECO:0000269|PubMed:18952128, ECO:0000269|PubMed:19494296, ECO:0000269|PubMed:22099304, ECO:0000269|PubMed:23827681, ECO:0000269|PubMed:8692885, ECO:0000269|PubMed:9299557, ECO:0000269|PubMed:9882303}.
• Disease: DISEASE: Autoinflammatory syndrome, familial, Behcet-like (AISBL) [MIM:616744]: An autosomal dominant, autoinflammatory disorder with early onset, characterized by ulceration of mucosal surfaces, particularly in the oral and genital areas. Additional variable features include skin rash, uveitis, and polyarthritis. {ECO:0000269|PubMed:26642243, ECO:0000269|PubMed:27175295}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: TNF signaling pathway - Homo sapiens (human);Necroptosis - Homo sapiens (human);NOD-like receptor signaling pathway - Homo sapiens (human);IL-17 signaling pathway - Homo sapiens (human);Measles - Homo sapiens (human);NF-kappa B signaling pathway - Homo sapiens (human);Epstein-Barr virus infection - Homo sapiens (human);Regulation of toll-like receptor signaling pathway;TNF alpha Signaling Pathway;Vitamin D Receptor Pathway;Glucocorticoid Receptor Pathway;Nuclear Receptors Meta-Pathway;Signal Transduction;tnfr2 signaling pathway;cd40l signaling pathway;NOD1/2 Signaling Pathway;Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways;Post-translational protein modification;DDX58/IFIH1-mediated induction of interferon-alpha/beta;Metabolism of proteins;Innate Immune System;Immune System;TNFR1-induced NFkappaB signaling pathway;TNFR1-induced proapoptotic signaling;TNF signaling;Negative regulators of DDX58/IFIH1 signaling;Ovarian tumor domain proteases;Deubiquitination;Death Receptor Signalling;Regulation of TNFR1 signaling;TNFalpha;Canonical NF-kappaB pathway;CD40/CD40L signaling;TNF receptor signaling pathway (Consensus)

Recessive Scores

• pRec: 0.611

Intolerance Scores

• loftool: 0.141
• rvis_EVS: -0.53
• rvis_percentile_EVS: 20.82

Haploinsufficiency Scores

• pHI: 0.315
• hipred: Y
• hipred_score: 0.825
• ghis: 0.563

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.973

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Tnfaip3
• Phenotype: cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); liver/biliary system phenotype; respiratory system phenotype; immune system phenotype; renal/urinary system phenotype; skeleton phenotype; digestive/alimentary phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: tnfaip3
• Affected structure: pharyngeal arch cartilage
• Phenotype tag: abnormal
• Phenotype quality: malformed

Gene ontology

• Biological process: B-1 B cell homeostasis;response to molecule of bacterial origin;regulation of germinal center formation;negative regulation of chronic inflammatory response;apoptotic process;inflammatory response;cytoskeleton organization;regulation of tumor necrosis factor-mediated signaling pathway;cell migration;protein deubiquitination;positive regulation of Wnt signaling pathway;negative regulation of protein ubiquitination;negative regulation of NF-kappaB transcription factor activity;negative regulation of type I interferon production;response to muramyl dipeptide;negative regulation of interleukin-2 production;negative regulation of interleukin-6 production;negative regulation of tumor necrosis factor production;negative regulation of toll-like receptor 2 signaling pathway;negative regulation of toll-like receptor 3 signaling pathway;negative regulation of toll-like receptor 4 signaling pathway;negative regulation of toll-like receptor 5 signaling pathway;protein K29-linked deubiquitination;protein K11-linked deubiquitination;negative regulation of I-kappaB kinase/NF-kappaB signaling;positive regulation of protein catabolic process;negative regulation of cyclin-dependent protein serine/threonine kinase activity;negative regulation of bone resorption;negative regulation of innate immune response;negative regulation of smooth muscle cell proliferation;regulation of defense response to virus by host;negative regulation of interleukin-1 beta secretion;negative regulation of inflammatory response;negative regulation of B cell activation;protein complex oligomerization;regulation of vascular wound healing;cellular response to hydrogen peroxide;nucleotide-binding oligomerization domain containing signaling pathway;negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway;negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway;protein K63-linked deubiquitination;protein K48-linked ubiquitination;protein K48-linked deubiquitination;cellular response to lipopolysaccharide;protein deubiquitination involved in ubiquitin-dependent protein catabolic process;tolerance induction to lipopolysaccharide;establishment of protein localization to vacuole;negative regulation of osteoclast proliferation;negative regulation of extrinsic apoptotic signaling pathway via death domain receptors;positive regulation of cellular protein catabolic process;protein K33-linked deubiquitination;positive regulation of hepatocyte proliferation;negative regulation of CD40 signaling pathway;negative regulation of endothelial cell apoptotic process
• Cellular component: nucleus;cytoplasm;lysosome;cytosol;intracellular membrane-bounded organelle;extracellular exosome
• Molecular function: protease binding;DNA binding;ubiquitin-protein transferase activity;thiol-dependent ubiquitin-specific protease activity;protein binding;zinc ion binding;kinase binding;thiol-dependent ubiquitinyl hydrolase activity;identical protein binding;ubiquitin binding;protein self-association;Lys63-specific deubiquitinase activity;K63-linked polyubiquitin modification-dependent protein binding