IKZF3

protein-coding

IKAROS family zinc finger 3, the group of Zinc fingers C2H2-type

Gene summary

This gene encodes a member of the Ikaros family of zinc-finger proteins. Three members of this protein family (Ikaros, Aiolos and Helios) are hematopoietic-specific transcription factors involved in the regulation of lymphocyte development. This gene product is a transcription factor that is important in the regulation of B lymphocyte proliferation and differentiation. Both Ikaros and Aiolos can participate in chromatin remodeling. Regulation of gene expression in B lymphocytes by Aiolos is complex as it appears to require the sequential formation of Ikaros homodimers, Ikaros/Aiolos heterodimers, and Aiolos homodimers. Several alternative transcripts encoding different isoforms have been described, as well as some non-protein coding variants. [provided by RefSeq, Apr 2012]

Previous symbols:

ZNFN1A3

MANE transcript

NM_012481.5

Inheritance

ClinVar variants

P:3U:63B:7

Top phenotype

Immunodeficiency 84

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr17:39,757,715-39,864,312

External References & Databases

Ensembl (ENSG00000161405)

Transcript & Mutation Effects

hg38 • Region Span ~106.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 84STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030333

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency 84LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0030333

Submitter: Ambry Genetics

immunodeficiency 84MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0030333

Submitter: ClinGen

The IKZF3 gene encodes the transcription factor Aiolos. Aiolos is a member of the Ikaros family; as a transcription factor, it can bind DNA in essential regions to control hematopoiesis and cell functions of immune cells. Immunodeficiency 84 or immunodeficiency due to IKZF3 deficiency (MONDO:0030333), is characterized by profound defects in B cell differentiation, and severe hypogammaglobulinemia in patients. A total of two missense variants have been reported in 7 patients in 2 publications only (PMID: 34155405, 34694366). The two variants: p.G159R and p.N160S were found in autosomal dominant traits. Experimental evidence includes loss of the ability to form pericentromeric heterochromatin foci in the dimer IKZF1-IKZF3 affecting the transcriptional activity of genes under IKZF3 regulation. Additionally, the Aiolos knock in mice evaluating the homologous variants for p.G159R, and p.N160S showed that mice have profound defects in B cell development and low immunoglobulin levels (IgG, IgM and IgA), which is consistent with the phenotype seen in patients. In summary, there is moderate evidence to support this gene-disease relationship with only two variants identified in two publications. Note from SCID-CID GCEP added 11/06/2026: IKZF3 (encoding the transcription factor AIOLOS) is a member of the IKAROS zinc finger family located on chromosome 17q21. Germline IKZF3 variants are associated primarily with defects in B cell development and function, though combined immunodeficiency and immune dysregulation phenotypes are also critical features, and the latter includes malignancies, autoimmunity and atopy (PMID: 34265590; PMID: 35444653).

immunodeficiency 84STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030333

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Immunodeficiency 84AD

Manifestation: Allergy/Immunology/Infectious; Oncologic

Intervention: Allergy/Immunology/Infectious; Oncologic

Rationale: Individuals may be susceptible to infections, and early and aggressive treatment of infections may be beneficial; Lymphoma has been described, and awareness may allow early detection and management; BMT has been described

Refs: 34155405

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IKZF3 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 55

not providedTotal: 6

Immunodeficiency 84Total: 6

IKZF3-related conditionTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012481.5. 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				4 clinvar	1 clinvar	5
missense	1 clinvar		61 clinvar	2 clinvar		64
nonsense			1 clinvar			1
start loss		1 clinvar				1
frameshift		1 clinvar				1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	1	2	63	6	1	73

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 45 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012481.5	RefSeq	NP_036613.2	8	MANE Select
ENST00000346872.8	Ensembl	ENSP00000344544.3	8	MANE Select
NM_001257408.2	RefSeq	NP_001244337.1	7	Standard
NM_001257409.2	RefSeq	NP_001244338.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

il-2 receptor beta chain in t cell activation
IL2-mediated signaling events

Biological Process

regulation of transcription by RNA polymerase II
mesoderm development
response to bacterium
regulation of B cell proliferation
B cell activation

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
DNA-binding transcription factor activity
protein binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000346872
Coding exons: 8
Length: 99244
Individuals with no LoFs: 125723
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125728
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.14	203	309	0.657	0.0000185	3420
Missense (PolyPhen)		47	137.84	0.34097		1481
Synonymous	0.374	105	110	0.955	0.00000695	892
Loss of Function	3.89	2	21.4	0.0934	0.00000106	286

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor that plays an important role in the regulation of lymphocyte differentiation. Plays an essential role in regulation of B-cell differentiation, proliferation and maturation to an effector state. Involved in regulating BCL2 expression and controlling apoptosis in T-cells in an IL2- dependent manner. {ECO:0000269|PubMed:10369681}.;

Recessive Scores

pRec: 0.211

Intolerance Scores

LoFtool: 0.116
RVIS EVS: -0.34
RVIS percentile EVS: 30.56

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.853

Gene Damage Prediction

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