TIFA
protein-codingTRAF interacting protein with forkhead associated domain
Gene summary
This gene encodes an adapter protein involved in adaptive and innate immunity. This protein includes a forkhead-associated (FHA) domain that specifically binds to phosphorylated serine and threonine residues. In response to bacterial infection, the encoded host cell protein undergoes an intermolecular interaction between the FHA domain and a phosphorylated threonine that leads to protein oligomerization and stimulation of the NF-kappa B and other downstream signaling pathways. This protein exhibits reduced expression in hepatocellular carcinoma and may suppress hepatocellular carcinoma progression. This protein may also play a role in the DNA damage response. [provided by RefSeq, Jun 2018]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~13.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TIFA variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_052864.3. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 0 | |||||
| missense | 18 | 18 | ||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 18 | 0 | 0 | 18 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_443096.1 | 1 | MANE Select | |
| Ensembl | ENSP00000354911.2 | 1 | MANE Select | |
| Ensembl | ENSP00000424231.1 | 1 | Standard | |
| Ensembl | ENSP00000424231.1 | 1 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Regulation of toll-like receptor signaling pathway
- Interleukin-1 Induced Activation of NF-kappa-B
- Simplified Depiction of MYD88 Distinct Input-Output Pathway
- TNFalpha
Biological Process
- cytoplasmic pattern recognition receptor signaling pathway
- I-kappaB kinase/NF-kappaB signaling
- positive regulation of I-kappaB kinase/NF-kappaB signaling
- innate immune response
- protein homooligomerization
Molecular Function
- protein binding
Cellular Component
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000361717
- Coding exons
- 1
- Length
- 11362
- Individuals with no LoFs
- 125615
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 104
- Defined
- 125719
- p
- 0.000414
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.895 | 71 | 95.6 | 0.743 | 0.00000472 | 1219 |
| Missense (PolyPhen) | 23 | 29.093 | 0.79058 | 389 | ||
| Synonymous | 0.386 | 35 | 38.0 | 0.920 | 0.00000219 | 327 |
| Loss of Function | 1.37 | 2 | 5.45 | 0.367 | 4.02e-7 | 52 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000075 | 0.000070 | rare |
| South Asian | 0.0030 | 0.0030 | notable |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Adapter molecule that plays a key role in the activation of proinflammatory NF-kappa-B signaling following detection of bacterial pathogen-associated molecular pattern metabolites (PAMPs) (PubMed:12566447, PubMed:15492226, PubMed:26068852, PubMed:28877472, PubMed:28222186, PubMed:30111836). Promotes activation of an innate immune response by inducing the oligomerization and polyubiquitination of TRAF6, which leads to the activation of TAK1 and IKK through a proteasome-independent mechanism (PubMed:15492226, PubMed:26068852). TIFA-dependent innate immune response is triggered by ADP-D-glycero-beta-D-manno- heptose (ADP-Heptose), a potent PAMP present in all Gram-negative and some Gram-positive bacteria: ADP-Heptose is recognized by ALPK1, which phosphorylates TIFA at Thr-9, leading to TIFA homooligomerization and subsequent activation of proinflammatory NF-kappa-B signaling (PubMed:30111836). {ECO:0000269|PubMed:12566447, ECO:0000269|PubMed:15492226, ECO:0000269|PubMed:26068852, ECO:0000269|PubMed:28222186, ECO:0000269|PubMed:28877472, ECO:0000269|PubMed:30111836}.;
Recessive Scores
- pRec
- 0.0854
Intolerance Scores
- LoFtool
- 0.550
- RVIS EVS
- -0.03
- RVIS percentile EVS
- 51.4
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.871
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |