NFKBIA
protein-codingNFKB inhibitor alpha, the group of Ankyrin repeat domain containing
Gene summary
This gene encodes a member of the NF-kappa-B inhibitor family, which contain multiple ankrin repeat domains. The encoded protein interacts with REL dimers to inhibit NF-kappa-B/REL complexes which are involved in inflammatory responses. The encoded protein moves between the cytoplasm and the nucleus via a nuclear localization signal and CRM1-mediated nuclear export. Mutations in this gene have been found in ectodermal dysplasia anhidrotic with T-cell immunodeficiency autosomal dominant disease. [provided by RefSeq, Aug 2011]
- NFKBI
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~3.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0012806
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0012806
Submitter: ClinGen
***NFKBIA*** was first reported in relation to autosomal-dominant anhidrotic ectodermal dysplasia with immune deficiency (AD-EDA-ID) in 2003 (Courtois et al., PMID: 14523047). *NFKBIA* is an inhibitor of NF-κB and encodes the protein IκBα. When the IκB kinase (IKK) complex phosphorylates IκBα at specific serine residues thereby promoting its ubiquitnation and degradation by the proteasome, the NF-κB complex is released and allowed to translocate into the nucleus and activate target genes. AD-EDA-ID is a form of ectodermal dysplasia, a group of conditions defined by abnormal development of ectodermal tissues including skin, hair, and sweat glands. Additionally, patients with EDA-ID often have reduced immune functions, with a combined T and B cell immunodeficiency alongside impaired monocyte and neutrophil responses to TLR stimulation, leading to susceptibility to bacterial, fungal, viral, and other opportunistic infections. Symptoms are evident soon after birth, with variable severity. 14 variants (11 missense and 3 nonsense) that have been reported in 18 probands in 16 publications (PMIDs: 23864385, 14523047, 23708964, 17931563, 22078572, 18412279, 23870671, 29948576, 35005117, 28417298, 28629746, 31683054, 32222431, 36292785, 15337789, 26691317) are included in this curation. Case-Level evidence supports this gene-disease relationship, with the majority of variants being de novo and having functional evidence. The mechanism of pathogenicity is reported to be gain of function due to increased resistance to degradation. This gene-disease relationship is also supported by mouse models, in vitro functional assays, expression studies, and biochemical function (PMIDs: 23864385, 14523047, 23708964, 25601653). A mouse model was made to be heterozygous for S32I mutation in *NFKBIA* (PMID: 25601653). This mouse has many features that reflect the presentation of EDA-ID seen in patients with *NFKBIA* mutations, including teeth and hair abnormalities and impaired immune responses. The in vitro functional assays and expression studies further support the role of *NFKBIA* mutations in the disease by demonstrating a connection to altered NF-kB signaling. More evidence is available in the literature, but the maximum score for experimental evidence (6 pts.) has been reached. In summary, there is definitive evidence supporting the relationship between *NFKBIA* and AD-EDA-ID. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen SCID-CID GCEP on the meeting date January 16th, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0012806
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0010293
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Dental; Dermatologic; Gastrointestinal
Intervention: Allergy/Immunology/Infectious
Rationale: In addition to ectodermal manifestations, individuals have immunodeficiency, and surveillance/prophylaxis/aggressive treatments of infection may be beneficial; BMT has been reported as effective
Comments: Syndromic features may not be clinically recognizable prior to infectious manifestations
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NFKBIA variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_020529.3. 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 | 91 | 2 | 93 | |||
| missense | 6 | 1 | 148 | 22 | 6 | 183 |
| nonsense | 3 | 2 | 1 | 6 | ||
| start loss | 1 | 1 | 1 | 3 | ||
| frameshift | 2 | 1 | 3 | |||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 9 | 4 | 153 | 115 | 8 | 289 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_065390.1 | 6 | MANE Select | |
| Ensembl | ENSP00000216797.6 | 6 | MANE Select | |
| Ensembl | ENSP00000451281.2 | 7 | Standard | |
| Ensembl | ENSP00000450537.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| nfkbiaa | Danio rerio | Structure: T cell Quality: increased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Chronic myeloid leukemia - Homo sapiens (human)
- Relaxin signaling pathway - Homo sapiens (human)
- Adipocytokine signaling pathway - Homo sapiens (human)
- T cell receptor signaling pathway - Homo sapiens (human)
- B cell receptor signaling pathway - Homo sapiens (human)
Biological Process
- obsolete protein import into nucleus, translocation
- apoptotic process
- I-kappaB kinase/NF-kappaB signaling
- cytoplasmic sequestering of NF-kappaB
- negative regulation of macrophage derived foam cell differentiation
Molecular Function
- protein binding
- transcription factor binding
- nuclear localization sequence binding
- enzyme binding
- ubiquitin protein ligase binding
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
- cytosol
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000216797
- Coding exons
- 6
- Length
- 3239
- Individuals with no LoFs
- 125745
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 125748
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.707 | 141 | 167 | 0.846 | 0.00000875 | 2051 |
| Missense (PolyPhen) | 40 | 62.344 | 0.6416 | 778 | ||
| Synonymous | -2.68 | 101 | 72.1 | 1.40 | 0.00000376 | 633 |
| Loss of Function | 3.64 | 0 | 15.5 | 0.00 | 7.79e-7 | 169 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Inhibits the activity of dimeric NF-kappa-B/REL complexes by trapping REL dimers in the cytoplasm through masking of their nuclear localization signals. On cellular stimulation by immune and proinflammatory responses, becomes phosphorylated promoting ubiquitination and degradation, enabling the dimeric RELA to translocate to the nucleus and activate transcription. {ECO:0000269|PubMed:7479976}.;
- Disease
- DISEASE: Ectodermal dysplasia, anhidrotic, with T-cell immunodeficiency autosomal dominant (ADEDAID) [MIM:612132]: A form of ectoderma dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. This form of ectodermal dysplasia is associated with decreased production of pro-inflammatory cytokines and certain interferons, rendering patients susceptible to infection. {ECO:0000269|PubMed:14523047, ECO:0000269|PubMed:18412279}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.926
Intolerance Scores
- LoFtool
- 0.0566
- RVIS EVS
- -0.27
- RVIS percentile EVS
- 34.32
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.999
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |