TRAF3

TNF receptor associated factor 3, the group of Zinc fingers TRAF-type|TNF receptor associated factors|Ring finger proteins

Basic information

Region (hg38): 14:102777449-102911500

Links

ENSG00000131323 ∙ NCBI:7187 ∙ OMIM:601896 ∙ HGNC:12033 ∙ Uniprot:Q13114 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• TRAF3 haploinsufficiency (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Encephalopathy, acute, infection-induceed (herpes-specific), susceptibility to, 5	AD	Allergy/Immunology/Infectious	Individuals may be susceptible to severe herpes simplex virus infections (eg, herpes encephalitis has been described), and awareness may allow early diagnosis and treatment (eg, with acyclovir, which has been reported as effective in the reported individual), potentially decreasing morbidity and mortality	Allergy/Immunology/Infectious	20832341

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TRAF3 gene.

• TRAF3 haploinsufficiency (1 variants)
• Herpes simplex encephalitis, susceptibility to, 3 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TRAF3 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			1	96	10	107
missense			134	1	1	136
nonsense	1		5			6
start loss						0
frameshift	1		6			7
inframe indel			1			1
splice donor/acceptor (+/-2bp)						0
splice region			7	13	1	21
non coding			1	56	11	68
Total	2	0	148	153	22

Variants in TRAF3

This is a list of pathogenic ClinVar variants found in the TRAF3 region.

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

Position	Type	Phenotype	Significance	ClinVar
14-102870208-T-C		Herpes simplex encephalitis, susceptibility to, 3	Uncertain significance (Feb 21, 2023)
14-102870210-G-C		Herpes simplex encephalitis, susceptibility to, 3 • TRAF3-related disorder	Likely benign (Nov 03, 2020)
14-102870217-A-G		Herpes simplex encephalitis, susceptibility to, 3	Uncertain significance (Jan 25, 2021)
14-102870226-T-A		Herpes simplex encephalitis, susceptibility to, 3	Uncertain significance (Nov 21, 2023)
14-102870229-C-A		Herpes simplex encephalitis, susceptibility to, 3	Uncertain significance (Mar 28, 2021)
14-102870229-C-T		Herpes simplex encephalitis, susceptibility to, 3	Uncertain significance (May 16, 2023)
14-102870230-C-T		not specified • Herpes simplex encephalitis, susceptibility to, 3	Uncertain significance (Apr 12, 2024)
14-102870235-G-A		Herpes simplex encephalitis, susceptibility to, 3 • not specified	Conflicting classifications of pathogenicity (Dec 30, 2023)
14-102870236-C-T		Herpes simplex encephalitis, susceptibility to, 3	Uncertain significance (Jan 29, 2024)
14-102870237-G-A		Herpes simplex encephalitis, susceptibility to, 3	Likely benign (Feb 04, 2022)
14-102870243-G-C		Herpes simplex encephalitis, susceptibility to, 3	Uncertain significance (Jan 05, 2024)
14-102870251-C-T		Herpes simplex encephalitis, susceptibility to, 3	Uncertain significance (Feb 25, 2023)
14-102870252-G-A		Herpes simplex encephalitis, susceptibility to, 3	Likely benign (Dec 24, 2022)
14-102870254-C-G		Ependymoma	Uncertain significance (Dec 29, 2017)
14-102870254-C-T		not specified	Uncertain significance (May 02, 2024)
14-102870255-G-A		Herpes simplex encephalitis, susceptibility to, 3	Likely benign (Nov 24, 2023)
14-102870258-A-G		Herpes simplex encephalitis, susceptibility to, 3	Likely benign (Nov 08, 2022)
14-102870268-A-G		Herpes simplex encephalitis, susceptibility to, 3	Uncertain significance (Apr 29, 2023)
14-102870274-C-T		Herpes simplex encephalitis, susceptibility to, 3	Uncertain significance (Jan 19, 2024)
14-102870275-G-A		Herpes simplex encephalitis, susceptibility to, 3 • TRAF3-related disorder	Uncertain significance (Dec 25, 2023)
14-102870275-G-T		Herpes simplex encephalitis, susceptibility to, 3	Uncertain significance (Nov 10, 2023)
14-102870277-A-C		not specified	Uncertain significance (Jul 17, 2023)
14-102870280-G-C		Herpes simplex encephalitis, susceptibility to, 3	Uncertain significance (Mar 15, 2022)
14-102870287-C-T		Herpes simplex encephalitis, susceptibility to, 3	Uncertain significance (Sep 17, 2023)
14-102870288-G-A		Herpes simplex encephalitis, susceptibility to, 3	Likely benign (Aug 14, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TRAF3	protein_coding	protein_coding	ENST00000560371	10	134025

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.999	0.00131	125743	0	4	125747	0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.99	184	339	0.543	0.0000227	3799
Missense in Polyphen		20	113.85	0.17567		1273
Synonymous	-1.06	154	138	1.12	0.0000102	1022
Loss of Function	4.56	2	28.1	0.0711	0.00000152	325

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000354	0.0000352
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Regulates pathways leading to the activation of NF- kappa-B and MAP kinases, and plays a central role in the regulation of B-cell survival. Part of signaling pathways leading to the production of cytokines and interferon. Required for normal antibody isotype switching from IgM to IgG. Plays a role T-cell dependent immune responses. Plays a role in the regulation of antiviral responses. Is an essential constituent of several E3 ubiquitin-protein ligase complexes. May have E3 ubiquitin-protein ligase activity and promote 'Lys-63'-linked ubiquitination of target proteins. Inhibits activation of NF-kappa-B in response to LTBR stimulation. Inhibits TRAF2-mediated activation of NF-kappa- B. Down-regulates proteolytic processing of NFKB2, and thereby inhibits non-canonical activation of NF-kappa-B. Promotes ubiquitination and proteasomal degradation of MAP3K14. {ECO:0000269|PubMed:15084608, ECO:0000269|PubMed:15383523, ECO:0000269|PubMed:17991829, ECO:0000269|PubMed:19937093, ECO:0000269|PubMed:20097753, ECO:0000269|PubMed:20185819}.
• Disease: DISEASE: Encephalopathy, acute, infection-induced, Herpes- specific, 5 (IIAE5) [MIM:614849]: A rare complication of human herpesvirus 1 (HHV-1) infection, occurring in only a small minority of HHV-1 infected individuals. It is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome. {ECO:0000269|PubMed:20832341}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
• Pathway: Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human);Small cell lung cancer - Homo sapiens (human);TNF signaling pathway - Homo sapiens (human);Toll-like receptor signaling pathway - Homo sapiens (human);NOD-like receptor signaling pathway - Homo sapiens (human);IL-17 signaling pathway - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Viral carcinogenesis - Homo sapiens (human);Hepatitis C - Homo sapiens (human);NF-kappa B signaling pathway - Homo sapiens (human);Epstein-Barr virus infection - Homo sapiens (human);RIG-I-like receptor signaling pathway - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Herpes simplex infection - Homo sapiens (human);Regulation of toll-like receptor signaling pathway;Apoptosis Modulation and Signaling;RANKL-RANK (Receptor activator of NFKB (ligand)) Signaling Pathway;TNF related weak inducer of apoptosis (TWEAK) Signaling Pathway;IL17 signaling pathway;Apoptosis;Apoptotic Signaling Pathway;TLR4 Signaling and Tolerance;Toll-like Receptor Signaling;RIG-I-like Receptor Signaling;Oxidative Damage;Toll-like Receptor Signaling Pathway;TWEAK;tnfr2 signaling pathway;cd40l signaling pathway;yaci and bcma stimulation of b cell immune responses;TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway;TNFR2 non-canonical NF-kB pathway;Cytokine Signaling in Immune system;TICAM1-dependent activation of IRF3/IRF7;Toll Like Receptor 3 (TLR3) Cascade;Toll-Like Receptors Cascades;Post-translational protein modification;DDX58/IFIH1-mediated induction of interferon-alpha/beta;Metabolism of proteins;Innate Immune System;Immune System;TRAF3-dependent IRF activation pathway;Negative regulators of DDX58/IFIH1 signaling;Ovarian tumor domain proteases;Deubiquitination;TNFalpha;Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon;TRIF(TICAM1)-mediated TLR4 signaling ;MyD88-independent TLR4 cascade ;Toll Like Receptor 4 (TLR4) Cascade;RANKL;CD40/CD40L signaling (Consensus)

Recessive Scores

• pRec: 0.298

Intolerance Scores

• rvis_EVS: -0.45
• rvis_percentile_EVS: 24.33

Haploinsufficiency Scores

• pHI: 0.144
• hipred: Y
• hipred_score: 0.825
• ghis: 0.569

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.994

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Traf3
• 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); hematopoietic system phenotype; liver/biliary system phenotype; renal/urinary system phenotype; immune system phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: regulation of cytokine production;toll-like receptor signaling pathway;apoptotic process;signal transduction;Toll signaling pathway;protein ubiquitination;protein deubiquitination;regulation of proteolysis;negative regulation of NF-kappaB transcription factor activity;regulation of interferon-beta production;tumor necrosis factor-mediated signaling pathway;TRIF-dependent toll-like receptor signaling pathway;regulation of apoptotic process;innate immune response;regulation of defense response to virus
• Cellular component: mitochondrion;endosome;cytosol;cytoplasmic side of plasma membrane;protein-containing complex;CD40 receptor complex
• Molecular function: ubiquitin-protein transferase activity;tumor necrosis factor receptor binding;protein binding;zinc ion binding;protein kinase binding;protein phosphatase binding;ubiquitin protein ligase binding;thioesterase binding