GeneBe

TRAF3IP2

protein-coding

TRAF3 interacting protein 2

Gene summary

This gene encodes a protein involved in regulating responses to cytokines by members of the Rel/NF-kappaB transcription factor family. These factors play a central role in innate immunity in response to pathogens, inflammatory signals and stress. This gene product interacts with TRAF proteins (tumor necrosis factor receptor-associated factors) and either I-kappaB kinase or MAP kinase to activate either NF-kappaB or Jun kinase. Several alternative transcripts encoding different isoforms have been identified. Another transcript, which does not encode a protein and is transcribed in the opposite orientation, has been identified. Overexpression of this transcript has been shown to reduce expression of at least one of the protein encoding transcripts, suggesting it has a regulatory role in the expression of this gene. [provided by RefSeq, Aug 2009]

Previous symbols:
  • C6orf4
  • C6orf5
  • C6orf6
  • C6orf2

MANE transcript

NM_147686.4

Inheritance

AR, AD

ClinVar variants

P:22U:153B:98

Top phenotype

Candidiasis, familial 8

gnomAD constraint

pLI —, LoF o/e 0.66

Max pathogenic AF

—

Genomic locus

chr6:111,555,381-111,606,906

External References & Databases

Ensembl (ENSG00000056972)NCBI Gene (10758)OMIM (607043)HGNC:1343GenCCUniProt (O43734)AlphaFoldClinVar (TRAF3IP2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~51.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

candidiasis, familial, 8MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014230

Submitter: LiferaOmics

Genetic evidence – Published PMID: 24120361 – Family 1 – two affected sibs (counted as one proband). Case-level (AR homozygous; non-LOF start = 0.1; consanguineous family) = 0.1; Segregation (two affected sibs segregating with homozygous variant in AR model) = 0.5; Case-control = 0 Family 1 total = 0.6 PMID: 31292894 – Family 2 – one proband. Case-level (AR homozygous; non-LOF start = 0.1; consanguineous family) = 0.1; Segregation = 0; Case-control = 0 Family 2 total = 0.1 PMID: 33359359 – Family 3 – one proband. Case-level (AR homozygous; predicted null; loss-of-function mechanism plausible; no consanguinity deduction applied [not reported]) = 1.5; Segregation = 0; Case-control = 0 Family 3 total = 1.5 PMID: 33359359 – Family 4 – one proband. Case-level (AR homozygous; predicted null; loss-of-function mechanism plausible; no consanguinity deduction applied [not reported]) = 1.5; Segregation = 0; Case-control = 0 Family 4 total = 1.5 PMID: 33825088 – Family 5 – one proband. Case-level (AR compound heterozygous; non-LOF start = 0.1; no consanguinity deduction applied [non-consanguineous]) = 0.1; Segregation = 0; Case-control = 0 Family 5 total = 0.1 PMID: 34289170 – Family 6 – one proband. Case-level (AR compound heterozygous; non-LOF; each variant evaluated independently; no consanguinity deduction applied [not reported]) = 0.2; Segregation = 0; Case-control = 0 Family 6 total = 0.2 Published genetic evidence total = 3.9 / 12 Genetic evidence – Our cases Family 1 – one proband. Case-level (AR homozygous; predicted null; loss-of-function mechanism plausible; no consanguinity deduction applied [not documented]) = 1.5; Segregation = 0; Case-control = 0 Family 1 total = 1.5 Family 2 – one proband. Case-level (AR homozygous; predicted null; loss-of-function mechanism plausible; no consanguinity deduction applied [not documented]) = 1.5; Segregation = 0; Case-control = 0 Family 2 total = 1.5 Family 3 – one proband. Case-level (AR homozygous; predicted null; loss-of-function mechanism plausible; no consanguinity deduction applied [not documented]) = 1.5; Segregation = 0; Case-control = 0 Family 3 total = 1.5 Our case total = 4.5 / 12 Total genetic evidence (published AR + our cases) 3.9 (published AR) + 4.5 (our cases) = 8.4 / 12 Experimental evidence – Published (conservative) PMID: 24120361 – Functional alteration (patient cells; IL-17 signaling defect). Patient primary cells showed absent response to IL-17A/F, demonstrating defective ACT1-dependent signaling. Functional alteration (strong patient-cell evidence) = 1.5 PMID: 33359359 – Functional alteration (additional patient-cell IL-17 signaling evidence; same pathway). Demonstrated loss of ACT1 protein and impaired downstream IL-17 responses. Functional alteration (supportive replication; same mechanistic category) = 0.5 PMID: 33825088 – Functional alteration (replication of IL-17 pathway impairment). Confirmed IL-17 signaling deficiency in additional individuals with biallelic variants. Functional alteration (additional supportive evidence) = 0.5 Experimental evidence total = 2.5 / 6 Overall score Genetic evidence = 12.0 Experimental evidence = 2.5 Overall score = 10.9 / 18 First report 2013 Subsequent publications 2019, 2020, 2021, 2022

chronic mucocutaneous candidiasisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015279

Submitter: Orphanet

candidiasis, familial, 8MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014230

Submitter: PanelApp Australia

candidiasis, familial, 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014230

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Candidiasis, familial 8AR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals have been reported as having recurrent candidal (and other) infections, and surveillance, prophylaxis, and early treatment may be beneficial

Refs: 24120361Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRAF3IP2 variants in ClinVar

6 Conditions Cataloged
Candidiasis, familial, 8Total: 277
not specifiedTotal: 76
not providedTotal: 10
TRAF3IP2-related disorderTotal: 9
Psoriasis 13, susceptibility toTotal: 6
Discoid lupus erythematosusTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_147686.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
79
clinvar
2
clinvar
 82
missense
2
clinvar
148
clinvar
16
clinvar
1
clinvar
 167
nonsense
6
clinvar
1
clinvar
2
clinvar
 9
start loss
0
frameshift
5
clinvar
2
clinvar
1
clinvar
 8
splice donor/acceptor (+/-2bp)
1
clinvar
5
clinvar
1
clinvar
 7
Total148153953273

Highest pathogenic variant AF is 0.000015503127

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_147686.4RefSeqNP_679211.28MANE Select
ENST00000368761.11EnsemblENSP00000357750.58MANE Select
NM_001164281.3RefSeqNP_001157753.18Standard
NM_001164283.3RefSeqNP_001157755.13Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • IL-17 signaling pathway - Homo sapiens (human)
  • Cellular senescence - Homo sapiens (human)
  • IL17 signaling pathway

Biological Process

  • B cell apoptotic process
  • positive regulation of defense response to virus by host
  • humoral immune response
  • intracellular signal transduction
  • positive regulation of I-kappaB kinase/NF-kappaB signaling

Molecular Function

  • signaling receptor binding
  • protein binding

Cellular Component

  • cellular_component

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000368761
Coding exons
8
Length
49825
Individuals with no LoFs
125698
Homozygous LoFs
0
Heterozygous LoFs
50
Defined
125748
p
0.000199
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.632353170.7420.00001673671
Missense (PolyPhen)5596.8620.567821178
Synonymous0.7801161270.9120.000007401143
Loss of Function1.651827.30.6600.00000161281

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000250.00025rare
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish00.0absent
East Asian0.000270.00027rare
Finnish0.000930.00092rare
European (Non-Finnish)0.000120.00011rare
South Asian0.000170.00016rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Could be involved in the activation of both NF-kappa-B via a NF-kappa-B inhibitor kinase (IKK)-dependent mechanism and stress-activated protein kinase (SAPK)/JNK.;
Disease
DISEASE: Candidiasis, familial, 8 (CANDF8) [MIM:615527]: A primary immunodeficiency disorder with altered immune responses and impaired clearance of fungal infections, selective against Candida. It is characterized by persistent and/or recurrent infections of the skin, nails and mucous membranes caused by organisms of the genus Candida, mainly Candida albicans. {ECO:0000269|PubMed:24120361}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.106

Intolerance Scores

LoFtool
0.893
RVIS EVS
1.29
RVIS percentile EVS
93.84

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.795

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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