NFKBIZ

protein-coding

NFKB inhibitor zeta, the group of Ankyrin repeat domain containing

Gene summary

This gene is a member of the ankyrin-repeat family and is induced by lipopolysaccharide (LPS). The C-terminal portion of the encoded product which contains the ankyrin repeats, shares high sequence similarity with the I kappa B family of proteins. The latter are known to play a role in inflammatory responses to LPS by their interaction with NF-B proteins through ankyrin-repeat domains. Studies in mouse indicate that this gene product is one of the nuclear I kappa B proteins and an activator of IL-6 production. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_031419.4

Inheritance

—

ClinVar variants

U:95B:9

Top phenotype

NFKBIZ-related disorder

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr3:101,827,991-101,861,022

External References & Databases

Ensembl (ENSG00000144802)

Transcript & Mutation Effects

hg38 • Region Span ~33.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary nonpolyposis colon cancerLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0018630

Submitter: ClinGen

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NFKBIZ variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 86

not providedTotal: 3

NFKBIZ-related disorderTotal: 2

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_031419.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	1 clinvar		2
missense			84 clinvar	8 clinvar		92
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			10 clinvar			10
Total	0	0	95	9	0	104

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_031419.4	RefSeq	NP_113607.1	12	MANE Select
ENST00000326172.9	Ensembl	ENSP00000325663.5	12	MANE Select
NM_001005474.3	RefSeq	NP_001005474.1	11	Standard
ENST00000326151.10	Ensembl	ENSP00000325593.5	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Transcriptional misregulation in cancer - Homo sapiens (human)
TNFalpha

Biological Process

inflammatory response
positive regulation of inflammatory response
T cell receptor signaling pathway
positive regulation of T-helper 17 cell differentiation

Molecular Function

protein binding

Cellular Component

nucleus
nuclear speck
cytoplasmic ribonucleoprotein granule

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000326172
Coding exons: 12
Length: 33032
Individuals with no LoFs: 125746
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125748
p: 0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.18	299	362	0.825	0.0000188	4695
Missense (PolyPhen)		60	105.5	0.56872		1355
Synonymous	-1.23	156	138	1.13	0.00000749	1405
Loss of Function	5.02	2	33.2	0.0602	0.00000169	372

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
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: dbNSFP

Function: FUNCTION: Involved in regulation of NF-kappa-B transcription factor complexes. Inhibits NF-kappa-B activity without affecting its nuclear translocation upon stimulation. Inhibits DNA-binding of RELA and NFKB1/p50, and of the NF-kappa-B p65-p50 heterodimer and the NF-kappa-B p50-p50 homodimer. Seems also to activate NF- kappa-B-mediated transcription. In vitro, upon association with NFKB1/p50 has transcriptional activation activity and, together with NFKB1/p50 and RELA, is recruited to LCN2 promoters. Promotes transcription of LCN2 and DEFB4. Is recruited to IL-6 promoters and activates IL-6 but decreases TNF-alpha production in response to LPS. Seems to be involved in the induction of inflammatory genes activated through TLR/IL-1 receptor signaling. May promote apoptosis (By similarity). Involved in the induction of T helper 17 cells (Th17) differentiation upon recognition of antigen by T cell antigen receptor (TCR) (By similarity). {ECO:0000250, ECO:0000250|UniProtKB:Q9EST8, ECO:0000269|PubMed:16513645, ECO:0000269|PubMed:16622025}.;

Recessive Scores

pRec: 0.0971

Intolerance Scores

RVIS EVS: -0.62
RVIS percentile EVS: 17.31

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.373

Gene Damage Prediction

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