NFKB1

nuclear factor kappa B subunit 1, the group of Ankyrin repeat domain containing|NF-kappa B complex subunits|IPT domain containing

Basic information

Region (hg38): 4:102501329-102617302

Links

ENSG00000109320 ∙ NCBI:4790 ∙ OMIM:164011 ∙ HGNC:7794 ∙ Uniprot:P19838 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• common variable immunodeficiency (Supportive), mode of inheritance: AD
• immunodeficiency, common variable, 12 (Strong), mode of inheritance: AD
• immunodeficiency, common variable, 12 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency, common variable, 12, with autoimmunity	AD	Allergy/Immunology/Infectious	Individuals have been described with immunodeficiency and recurrent infections, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial	Allergy/Immunology/Infectious	26279205

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NFKB1 gene.

• not provided (538 variants)
• Immunodeficiency, common variable, 12 (41 variants)
• Inborn genetic diseases (17 variants)
• not specified (10 variants)
• NFKB1-related condition (10 variants)
• Inherited Immunodeficiency Diseases (10 variants)
• Common variable immunodeficiency (6 variants)
• - (2 variants)
• High myopia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NFKB1 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			2	106	14	122
missense	4		197	11	4	216
nonsense	14	4				18
start loss			1			1
frameshift	41	12				53
inframe indel			5			5
splice donor/acceptor (+/-2bp)	1	23				24
splice region		1	8	14	7	30
non coding			6	55	39	100
Total	60	39	211	172	57

Highest pathogenic variant AF is 0.00000658

Variants in NFKB1

This is a list of pathogenic ClinVar variants found in the NFKB1 region.

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

Position	Type	Phenotype	Significance	ClinVar
4-102510933-A-G			Benign (Jun 01, 2023)
4-102525519-A-G			Uncertain significance (Nov 01, 2022)
4-102525537-T-C			Uncertain significance (Jun 09, 2022)
4-102525540-T-A			Uncertain significance (Mar 31, 2023)
4-102525542-G-A			Benign (Jan 06, 2024)
4-102525551-T-C			Likely benign (Jul 31, 2018)
4-102525557-A-G			Uncertain significance (Aug 04, 2023)
4-102525564-G-A			Likely benign (Oct 04, 2022)
4-102525565-T-C			Likely benign (Oct 05, 2023)
4-102525574-C-G			Benign (Feb 01, 2024)
4-102529821-T-C			Likely benign (Aug 28, 2022)
4-102529823-T-G			Likely benign (Jan 19, 2023)
4-102529826-T-G			Likely benign (Apr 14, 2022)
4-102529831-T-C			Likely benign (Feb 18, 2022)
4-102529834-A-G			Likely pathogenic (Sep 17, 2022)
4-102529836-A-T		Inborn genetic diseases	Uncertain significance (Aug 02, 2021)
4-102529837-T-C			Uncertain significance (Dec 01, 2022)
4-102529843-A-T			Uncertain significance (Dec 01, 2023)
4-102529845-T-G			Uncertain significance (Sep 02, 2022)
4-102529847-G-A			Likely benign (Jul 06, 2022)
4-102529852-C-T		Inborn genetic diseases	Conflicting classifications of pathogenicity (Nov 01, 2022)
4-102529860-A-G			Uncertain significance (Oct 12, 2022)
4-102529861-C-G			Uncertain significance (Mar 20, 2019)
4-102529863-C-G			Uncertain significance (Jun 14, 2022)
4-102529864-A-G			Uncertain significance (Oct 16, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NFKB1	protein_coding	protein_coding	ENST00000226574	23	115974

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.00000190	125735	0	3	125738	0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.19	337	547	0.616	0.0000291	6353
Missense in Polyphen		64	185.46	0.34509		2081
Synonymous	-0.0486	210	209	1.00	0.0000120	1926
Loss of Function	5.98	2	45.6	0.0439	0.00000219	567

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000177	0.0000176
Middle Eastern	0.0000544	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and RelB-p50 complexes are transcriptional activators. The NF-kappa-B p50-p50 homodimer is a transcriptional repressor, but can act as a transcriptional activator when associated with BCL3. NFKB1 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p105 and generation of p50 by a cotranslational processing. The proteasome-mediated process ensures the production of both p50 and p105 and preserves their independent function, although processing of NFKB1/p105 also appears to occur post-translationally. p50 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. In a complex with MAP3K8, NFKB1/p105 represses MAP3K8-induced MAPK signaling; active MAP3K8 is released by proteasome-dependent degradation of NFKB1/p105. {ECO:0000269|PubMed:15485931}.
• Disease: DISEASE: Immunodeficiency, common variable, 12 (CVID12) [MIM:616576]: A primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antigen. {ECO:0000269|PubMed:26279205}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: PI3K-Akt signaling pathway - Homo sapiens (human);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);Pertussis - Homo sapiens (human);Salmonella infection - Homo sapiens (human);Legionellosis - Homo sapiens (human);Neurotrophin signaling pathway - Homo sapiens (human);Insulin resistance - Homo sapiens (human);Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human);Doxorubicin Pathway (Cancer Cell), Pharmacodynamics;AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human);HIF-1 signaling pathway - Homo sapiens (human);Small cell lung cancer - Homo sapiens (human);Influenza A - Homo sapiens (human);Acute myeloid leukemia - Homo sapiens (human);Inflammatory bowel disease (IBD) - Homo sapiens (human);TNF signaling pathway - Homo sapiens (human);Chemokine signaling pathway - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);Amoebiasis - 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);Longevity regulating pathway - 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);Fluid shear stress and atherosclerosis - Homo sapiens (human);C-type lectin receptor signaling pathway - Homo sapiens (human);Tuberculosis - Homo sapiens (human);Th17 cell differentiation - Homo sapiens (human);Th1 and Th2 cell differentiation - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Leishmaniasis - Homo sapiens (human);IL-17 signaling pathway - Homo sapiens (human);Toxoplasmosis - Homo sapiens (human);Sphingolipid signaling pathway - Homo sapiens (human);Shigellosis - Homo sapiens (human);Prolactin signaling pathway - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Viral carcinogenesis - Homo sapiens (human);Transcriptional misregulation in cancer - 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);Cellular senescence - Homo sapiens (human);Epstein-Barr virus infection - Homo sapiens (human);Pancreatic cancer - Homo sapiens (human);RIG-I-like receptor signaling pathway - Homo sapiens (human);Cocaine addiction - Homo sapiens (human);EGFR Inhibitor Pathway, Pharmacodynamics;Human papillomavirus infection - Homo sapiens (human);Herpes simplex infection - Homo sapiens (human);Tacrolimus/Cyclosporine Pathway, Pharmacodynamics;Intracellular Signalling Through Adenosine Receptor A2b and Adenosine;Intracellular Signalling Through Adenosine Receptor A2a and Adenosine;Osteopontin Signaling;Regulation of toll-like receptor signaling pathway;Selenium Micronutrient Network;Vitamin B12 Metabolism;MicroRNAs in cardiomyocyte hypertrophy;TFs Regulate miRNAs related to cardiac hypertrophy;Folate Metabolism;Apoptosis Modulation and Signaling;IL-1 signaling pathway;RANKL-RANK (Receptor activator of NFKB (ligand)) Signaling Pathway;Leptin signaling pathway;TNF related weak inducer of apoptosis (TWEAK) Signaling Pathway;Prolactin Signaling Pathway;Neural Crest Differentiation;IL17 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;Quercetin and Nf-kB- AP-1 Induced Cell Apoptosis;Apoptosis;T-Cell Receptor and Co-stimulatory Signaling;Aryl Hydrocarbon Receptor;JAK-STAT;EBV LMP1 signaling;Cardiac Hypertrophic Response;Selenium Metabolism and Selenoproteins;Hair Follicle Development- Induction (Part 1 of 3);Apoptosis-related network due to altered Notch3 in ovarian cancer;IL1 and megakaryocytes in obesity;Myometrial Relaxation and Contraction Pathways;Melatonin metabolism and effects;Rac1-Pak1-p38-MMP-2 pathway;Initiation of transcription and translation elongation at the HIV-1 LTR;Photodynamic therapy-induced NF-kB survival signaling;NAD metabolism, sirtuins and aging;Apoptotic Signaling Pathway;Hepatitis C and Hepatocellular Carcinoma;MAPK Signaling Pathway;Apoptosis Modulation by HSP70;MAPK and NFkB Signalling Pathways Inhibited by Yersinia YopJ;Factors and pathways affecting insulin-like growth factor (IGF1)-Akt signaling;TLR4 Signaling and Tolerance;Toll-like Receptor Signaling;T-Cell antigen Receptor (TCR) pathway during Staphylococcus aureus infection;RIG-I-like Receptor Signaling;Simplified Depiction of MYD88 Distinct Input-Output Pathway;ATM Signaling Network in Development and Disease;IL-4 Signaling Pathway;VEGFA-VEGFR2 Signaling Pathway;Nanomaterial induced inflammasome activation;Chemokine signaling pathway;Oxidative Damage;Protein alkylation leading to liver fibrosis;miRNA regulation of prostate cancer signaling pathways;Prion disease pathway;NO-cGMP-PKG mediated Neuroprotection;Oxidative Stress;Fibrin Complement Receptor 3 Signaling Pathway;PI3K-Akt Signaling Pathway;Ebola Virus Pathway on Host;Ebola Virus Pathway on Host;Ras Signaling;TGF-beta Receptor Signaling;Notch Signaling Pathway;T-Cell antigen Receptor (TCR) Signaling Pathway;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;DNA Damage Response (only ATM dependent);Estrogen signaling pathway;Toll-like Receptor Signaling Pathway;RAGE;TLR NFkB;TWEAK;Toll Like Receptor 7/8 (TLR7/8) Cascade;Notch;Interleukin-17 signaling;Neutrophil degranulation;Signal Transduction;Signaling by Interleukins;p75NTR signals via NF-kB;nf-kb signaling 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;Senescence-Associated Secretory Phenotype (SASP);Cellular Senescence;Downstream TCR signaling;TCR signaling;Cellular responses to stress;TRAF6 mediated NF-kB activation;DDX58/IFIH1-mediated induction of interferon-alpha/beta;Activation of NF-kappaB in B cells;DEx/H-box helicases activate type I IFN and inflammatory cytokines production ;Signaling by the B Cell Receptor (BCR);Interleukin-1 signaling;CLEC7A (Dectin-1) signaling;PKMTs methylate histone lysines;CD209 (DC-SIGN) signaling;C-type lectin receptors (CLRs);Chromatin modifying enzymes;Fc epsilon receptor (FCERI) signaling;TCR;Oncostatin_M;Innate Immune System;Immune System;Adaptive Immune System;Fibroblast growth factor-1;Downstream signaling events of B Cell Receptor (BCR);IL-1 NFkB;CRH;IL1;RIP-mediated NFkB activation via ZBP1;Cellular responses to external stimuli;TAK1 activates NFkB by phosphorylation and activation of IKKs complex;MAP3K8 (TPL2)-dependent MAPK1/3 activation;BDNF;EGFR1;MAP kinase activation;TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation;Glucocorticoid receptor regulatory network;MyD88 dependent cascade initiated on endosome;BCR signaling pathway;IL2;NF-kB is activated and signals survival;Death Receptor Signalling;Chromatin organization;IL3;Regulated proteolysis of p75NTR;p75 NTR receptor-mediated signalling;Gastrin;Angiopoietin receptor Tie2-mediated signaling;IL4;EPO signaling pathway;IL5;FCERI mediated NF-kB activation;IL6;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;RANKL;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;TNF receptor signaling pathway ;Fc-epsilon receptor I signaling in mast cells;Regulation of Telomerase;IL2 signaling events mediated by PI3K;amb2 Integrin signaling;Interleukin-1 processing;IL1-mediated signaling events;Signaling events mediated by HDAC Class I;Alternative NF-kappaB pathway;Ceramide signaling pathway;IL12-mediated signaling events;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: 0.946

Intolerance Scores

• loftool: 0.307
• rvis_EVS: -0.48
• rvis_percentile_EVS: 22.78

Haploinsufficiency Scores

• pHI: 0.938
• hipred: Y
• hipred_score: 0.792
• ghis: 0.555

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nfkb1
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; craniofacial phenotype; growth/size/body region 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); endocrine/exocrine gland phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; respiratory system phenotype; immune system phenotype; skeleton phenotype; digestive/alimentary phenotype; hearing/vestibular/ear phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); hematopoietic system 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)

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;stimulatory C-type lectin receptor signaling pathway;transcription by RNA polymerase II;apoptotic process;inflammatory response;negative regulation of gene expression;positive regulation of macrophage derived foam cell differentiation;positive regulation of lipid storage;negative regulation of calcidiol 1-monooxygenase activity;negative regulation of vitamin D biosynthetic process;membrane protein intracellular domain proteolysis;negative regulation of cellular protein metabolic process;negative regulation of cholesterol transport;positive regulation of type I interferon production;response to muscle stretch;Fc-epsilon receptor signaling pathway;negative regulation of apoptotic process;neutrophil degranulation;negative regulation of interleukin-12 biosynthetic process;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;negative regulation of inflammatory response;T cell receptor signaling pathway;positive regulation of NF-kappaB transcription factor activity;stress-activated MAPK cascade;interleukin-1-mediated signaling pathway;cellular response to lipopolysaccharide;cellular response to mechanical stimulus;cellular response to nicotine;cellular response to interleukin-1;cellular response to interleukin-6;cellular response to tumor necrosis factor;cellular response to dsRNA;positive regulation of canonical Wnt signaling pathway;positive regulation of hyaluronan biosynthetic process;cellular response to angiotensin;positive regulation of miRNA metabolic process
• Cellular component: extracellular region;nucleus;nucleoplasm;cytoplasm;mitochondrion;cytosol;I-kappaB/NF-kappaB complex;secretory granule lumen;specific granule lumen
• Molecular function: transcription regulatory region sequence-specific DNA binding;RNA polymerase II regulatory region sequence-specific DNA binding;RNA polymerase II distal enhancer sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription repressor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;chromatin binding;DNA-binding transcription factor activity;protein binding;transcription factor binding;identical protein binding;protein homodimerization activity;actinin binding;transcription regulatory region DNA binding;protein heterodimerization activity