NFKBIA

NFKB inhibitor alpha, the group of Ankyrin repeat domain containing

Basic information

Region (hg38): 14:35401078-35404749

Previous symbols: [ "NFKBI" ]

Links

ENSG00000100906 ∙ NCBI:4792 ∙ OMIM:164008 ∙ HGNC:7797 ∙ Uniprot:P25963 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• ectodermal dysplasia and immunodeficiency 2 (Strong), mode of inheritance: AD
• ectodermal dysplasia and immune deficiency (Supportive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Ectodermal dysplasia and immunodeficiency 2	AD	Allergy/Immunology/Infectious	In addition to ectodermal manifestations, individuals have immunodeficiency, and surveillance/prophylaxis/aggressive treatments of infection may be beneficial; BMT has been reported as effective	Allergy/Immunology/Infectious; Dental; Dermatologic; Gastrointestinal	15337789; 16769798; 17931563; 18412279; 23708964; 23864385; 23870671; 26691317; 28417298; 28597146; 29948576
Syndromic features may not be clinically recognizable prior to infectious manifestations

ClinVar

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

• Ectodermal dysplasia and immunodeficiency 2 (224 variants)
• not provided (31 variants)
• not specified (11 variants)
• Inborn genetic diseases (7 variants)
• NFKBIA-related condition (2 variants)
• Inherited Immunodeficiency Diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NFKBIA 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	55	5	61
missense	1		89	9	5	104
nonsense	3					3
start loss		1	1			2
frameshift			1			1
inframe indel			3			3
splice donor/acceptor (+/-2bp)						0
splice region			5	6	1	12
non coding			7	19	24	50
Total	4	1	102	83	34

Variants in NFKBIA

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

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

Position	Type	Phenotype	Significance	ClinVar
14-35401592-C-T		Ectodermal dysplasia and immunodeficiency 2	Benign (Jan 13, 2018)
14-35401647-C-T		Ectodermal dysplasia and immunodeficiency 2	Uncertain significance (Jan 13, 2018)
14-35401711-T-G		Ectodermal dysplasia and immunodeficiency 2	Uncertain significance (Jun 14, 2016)
14-35401750-C-A		Ectodermal dysplasia and immunodeficiency 2	Benign (Jan 13, 2018)
14-35401761-A-C		Ectodermal dysplasia and immunodeficiency 2	Uncertain significance (Jan 13, 2018)
14-35401818-G-A		Ectodermal dysplasia and immunodeficiency 2	Benign (Jan 13, 2018)
14-35401869-C-CAA		Ectodermal dysplasia and immunodeficiency 2	Likely benign (Jun 14, 2016)
14-35401887-C-T		Ectodermal dysplasia and immunodeficiency 2 • not specified	Benign (Jan 24, 2024)
14-35401911-A-C		Ectodermal dysplasia and immunodeficiency 2	Uncertain significance (Feb 02, 2018)
14-35401914-A-T		Ectodermal dysplasia and immunodeficiency 2	Benign (Jan 13, 2018)
14-35401929-TTTC-T		Ectodermal dysplasia and immunodeficiency 2 • not specified	Benign (Nov 12, 2023)
14-35401995-C-G		Ectodermal dysplasia and immunodeficiency 2	Benign (Jan 12, 2018)
14-35402011-G-A		Ectodermal dysplasia and immunodeficiency 2 • not specified	Benign (Nov 12, 2023)
14-35402019-C-T		Ectodermal dysplasia and immunodeficiency 2 • NFKBIA-related disorder	Likely benign (Nov 27, 2023)
14-35402020-G-A		Ectodermal dysplasia and immunodeficiency 2	Uncertain significance (Jan 15, 2024)
14-35402023-A-C		Ectodermal dysplasia and immunodeficiency 2 • Inborn genetic diseases	Uncertain significance (May 22, 2023)
14-35402026-C-T		Ectodermal dysplasia and immunodeficiency 2	Benign (Dec 15, 2023)
14-35402027-G-A		Ectodermal dysplasia and immunodeficiency 2	Likely benign (Dec 22, 2023)
14-35402031-G-A		Ectodermal dysplasia and immunodeficiency 2	Likely benign (Jul 13, 2022)
14-35402040-C-G		Ectodermal dysplasia and immunodeficiency 2	Likely benign (Nov 17, 2023)
14-35402050-T-C		Ectodermal dysplasia and immunodeficiency 2	Uncertain significance (Nov 08, 2022)
14-35402055-G-C		Ectodermal dysplasia and immunodeficiency 2	Likely benign (Jan 08, 2024)
14-35402055-G-T		Ectodermal dysplasia and immunodeficiency 2	Likely benign (Sep 12, 2023)
14-35402056-G-C		Ectodermal dysplasia and immunodeficiency 2	Uncertain significance (Feb 06, 2023)
14-35402066-A-G		Ectodermal dysplasia and immunodeficiency 2	Likely benign (Nov 07, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NFKBIA	protein_coding	protein_coding	ENST00000216797	6	3239

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.995	0.00548	125745	0	3	125748	0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.707	141	167	0.846	0.00000875	2051
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000123	0.000123
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000879	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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);Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human);Legionellosis - Homo sapiens (human);Neurotrophin signaling pathway - Homo sapiens (human);Insulin resistance - Homo sapiens (human);Small cell lung cancer - Homo sapiens (human);Influenza A - Homo sapiens (human);TNF signaling pathway - Homo sapiens (human);Chemokine signaling pathway - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);Cytosolic DNA-sensing pathway - Homo sapiens (human);Epithelial cell signaling in Helicobacter pylori infection - Homo sapiens (human);Prostate cancer - Homo sapiens (human);Chagas disease (American trypanosomiasis) - Homo sapiens (human);Toll-like receptor signaling pathway - Homo sapiens (human);NOD-like receptor signaling pathway - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);C-type lectin receptor signaling pathway - Homo sapiens (human);Th17 cell differentiation - Homo sapiens (human);Th1 and Th2 cell differentiation - Homo sapiens (human);Leishmaniasis - Homo sapiens (human);IL-17 signaling pathway - Homo sapiens (human);Toxoplasmosis - Homo sapiens (human);Shigellosis - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Viral carcinogenesis - Homo sapiens (human);Hepatitis C - Homo sapiens (human);Hepatitis B - Homo sapiens (human);Measles - Homo sapiens (human);Osteoclast differentiation - Homo sapiens (human);Apoptosis - 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);Herpes simplex infection - Homo sapiens (human);Intracellular Signalling Through Adenosine Receptor A2b and Adenosine;Intracellular Signalling Through Adenosine Receptor A2a and Adenosine;Nucleotide-binding Oligomerization Domain (NOD) pathway;Regulation of toll-like receptor signaling pathway;Apoptosis Modulation and Signaling;IL-1 signaling pathway;RANKL-RANK (Receptor activator of NFKB (ligand)) Signaling Pathway;TNF related weak inducer of apoptosis (TWEAK) Signaling Pathway;Prolactin Signaling Pathway;Thymic Stromal LymphoPoietin (TSLP) Signaling Pathway;B Cell Receptor Signaling Pathway;TNF alpha Signaling Pathway;AGE-RAGE pathway;Corticotropin-releasing hormone signaling pathway;Oncostatin M Signaling Pathway;Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;Apoptosis;EBV LMP1 signaling;Rac1-Pak1-p38-MMP-2 pathway;Initiation of transcription and translation elongation at the HIV-1 LTR;Apoptotic Signaling Pathway;T-Cell antigen Receptor (TCR) pathway during Staphylococcus aureus infection;RIG-I-like Receptor Signaling;IL-4 Signaling Pathway;VEGFA-VEGFR2 Signaling Pathway;Chemokine signaling pathway;miRNA regulation of prostate cancer signaling pathways;NO-cGMP-PKG mediated Neuroprotection;T-Cell antigen Receptor (TCR) Signaling Pathway;Toll-like Receptor Signaling Pathway;RAGE;TLR NFkB;TWEAK;Toll Like Receptor 7/8 (TLR7/8) Cascade;double stranded rna induced gene expression;Signal Transduction;Signaling by Interleukins;p75NTR signals via NF-kB;mechanism of gene regulation by peroxisome proliferators via ppara;influence of ras and rho proteins on g1 to s transition;role of egf receptor transactivation by gpcrs in cardiac hypertrophy;chaperones modulate interferon signaling pathway;trefoil factors initiate mucosal healing;erythropoietin mediated neuroprotection through nf-kb;tnfr2 signaling pathway;akt signaling pathway;cd40l signaling pathway;acetylation and deacetylation of rela in nucleus;cadmium induces dna synthesis and proliferation in macrophages;hiv-1 nef: negative effector of fas and tnf;signal transduction through il1r;nf-kb signaling pathway;nfkb activation by nontypeable hemophilus influenzae;t cell receptor signaling pathway;keratinocyte differentiation;toll-like receptor pathway;Prolactin;Cytokine Signaling in Immune system;Toll Like Receptor 9 (TLR9) Cascade;MyD88 cascade initiated on plasma membrane;Toll Like Receptor 10 (TLR10) Cascade;Toll Like Receptor 3 (TLR3) Cascade;Toll Like Receptor 5 (TLR5) Cascade;B cell receptor signaling;ZBP1(DAI) mediated induction of type I IFNs;Toll-Like Receptors Cascades;Downstream TCR signaling;TCR signaling;Post-translational protein modification;TRAF6 mediated NF-kB activation;DDX58/IFIH1-mediated induction of interferon-alpha/beta;Activation of NF-kappaB in B cells;Metabolism of proteins;Signaling by the B Cell Receptor (BCR);Interleukin-1 signaling;CLEC7A (Dectin-1) signaling;C-type lectin receptors (CLRs);Fc epsilon receptor (FCERI) signaling;TCR;Oncostatin_M;Innate Immune System;Immune System;Ghrelin;Adaptive Immune System;inactivation of gsk3 by akt causes accumulation of b-catenin in alveolar macrophages;Downstream signaling events of B Cell Receptor (BCR);BCR;IL-1 NFkB;CRH;ceramide signaling pathway;Aurora A signaling;IL1;RIP-mediated NFkB activation via ZBP1;TAK1 activates NFkB by phosphorylation and activation of IKKs complex;atm signaling pathway;BDNF;TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation;fmlp induced chemokine gene expression in hmc-1 cells;MyD88 dependent cascade initiated on endosome;Ub-specific processing proteases;BCR signaling pathway;bone remodeling;Deubiquitination;NF-kB is activated and signals survival;Death Receptor Signalling;p75 NTR receptor-mediated signalling;Gastrin;IL4;IL5;Leptin;FCERI mediated NF-kB activation;TNFalpha;Cytosolic sensors of pathogen-associated DNA ;TRIF(TICAM1)-mediated TLR4 signaling ;MyD88-independent TLR4 cascade ;Toll Like Receptor 4 (TLR4) Cascade;TNF;Canonical NF-kappaB pathway;MyD88:Mal cascade initiated on plasma membrane;Toll Like Receptor TLR1:TLR2 Cascade;Toll Like Receptor TLR6:TLR2 Cascade;Toll Like Receptor 2 (TLR2) Cascade;Osteopontin-mediated events;IL23-mediated signaling events;HIV-1 Nef: Negative effector of Fas and TNF-alpha;CD40/CD40L signaling;LPA receptor mediated events;Signaling events mediated by HDAC Class I;Ceramide signaling pathway;Atypical NF-kappaB pathway;Interleukin-1 family signaling;CD4 T cell receptor signaling-NFkB cascade;TSLP;CD4 T cell receptor signaling (Consensus)

Recessive Scores

• pRec: 0.926

Intolerance Scores

• loftool: 0.0566
• rvis_EVS: -0.27
• rvis_percentile_EVS: 34.32

Haploinsufficiency Scores

• pHI: 0.900
• hipred: Y
• hipred_score: 0.783
• ghis: 0.506

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.999

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nfkbia
• Phenotype: endocrine/exocrine gland 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); growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype; normal 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; immune system phenotype

Zebrafish Information Network

• Gene name: nfkbiaa
• Affected structure: T cell
• Phenotype tag: abnormal
• Phenotype quality: increased amount

Gene ontology

• 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;positive regulation of cholesterol efflux;negative regulation of lipid storage;viral process;protein deubiquitination;lipopolysaccharide-mediated signaling pathway;negative regulation of NF-kappaB transcription factor activity;positive regulation of cellular protein metabolic process;response to muramyl dipeptide;tumor necrosis factor-mediated signaling pathway;toll-like receptor 4 signaling pathway;response to muscle stretch;regulation of cell population proliferation;cytoplasmic sequestering of transcription factor;negative regulation of apoptotic process;response to exogenous dsRNA;negative regulation of DNA binding;negative regulation of myeloid cell differentiation;negative regulation of Notch signaling pathway;positive regulation of transcription by RNA polymerase II;positive regulation of inflammatory response;cellular response to cold;nucleotide-binding oligomerization domain containing 1 signaling pathway;nucleotide-binding oligomerization domain containing 2 signaling pathway;interleukin-1-mediated signaling pathway;regulation of NIK/NF-kappaB signaling
• Cellular component: nucleus;nucleoplasm;cytoplasm;cytosol;plasma membrane;I-kappaB/NF-kappaB complex
• Molecular function: protein binding;transcription factor binding;nuclear localization sequence binding;enzyme binding;ubiquitin protein ligase binding;identical protein binding;NF-kappaB binding