NFE2L2

protein-coding

NFE2 like bZIP transcription factor 2, the group of Basic leucine zipper proteins|MicroRNA protein coding host genes

Gene summary

This gene encodes a transcription factor which is a member of a small family of basic leucine zipper (bZIP) proteins. The encoded transcription factor regulates genes which contain antioxidant response elements (ARE) in their promoters; many of these genes encode proteins involved in response to injury and inflammation which includes the production of free radicals. Multiple transcript variants encoding different isoforms have been characterized for this gene. [provided by RefSeq, Sep 2015]

MANE transcript

NM_006164.5

Inheritance

ClinVar variants

P:6U:233B:156

Top phenotype

Immunodeficiency, developmental delay, and hypohomocysteinemia

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr2:177,218,667-177,392,756

External References & Databases

Ensembl (ENSG00000116044)

Transcript & Mutation Effects

hg38 • Region Span ~174.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency, developmental delay, and hypohomocysteinemiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0060591

Submitter: G2P

immunodeficiency, developmental delay, and hypohomocysteinemiaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0060591

Submitter: ClinGen

*NFE2L2* was first reported in relation to autosomal dominant immunodeficiency, developmental delay, and hypohomocysteinemia (IMDDHH) in 2017 (Huppke P et al., PMID:29018201). IMDDHH is a multisystem disorder characterized by immunodeficiency, mildly delayed psychomotor development, poor overall growth from infancy, and hypohomocysteinemia. Patients may also present with additional features such as congenital heart defects, potential liver damage, subcortical T2-weighted white matter abnormalities and other more variable phenotypes. At least 4 variants (all missense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.

immunodeficiency, developmental delay, and hypohomocysteinemiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0060591

Submitter: PanelApp Australia

immunodeficiency, developmental delay, and hypohomocysteinemiaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0060591

Submitter: Illumina

immunodeficiency, developmental delay, and hypohomocysteinemiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0060591

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Immunodeficiency, developmental delay, and hypohomocysteinemiaAD

Manifestation: Allergy/Immunology/Infectious; Biochemical; Cardiovascular; Gastrointestinal; Neurologic

Intervention: Allergy/Immunology/Infectious; Biochemical

Rationale: The condition can manifest with immunodeficiency (for which antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial), liver damage, and other features, and medical management (with luteolin and ascorbic acid) has been described as beneficial related to certain parameters, such as liver enzymes and reported frequency of infections

Refs: 29018201

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NFE2L2 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 383

not specifiedTotal: 72

NFE2L2-related disorderTotal: 17

Immunodeficiency, developmental delay, and hypohomocysteinemiaTotal: 16

Neurodevelopmental abnormalityTotal: 1

Lung cancerTotal: 1

Colorectal cancerTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006164.5. 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			1 clinvar	99 clinvar	3 clinvar	103
missense	3 clinvar	3 clinvar	208 clinvar	27 clinvar	26 clinvar	267
nonsense			6 clinvar	1 clinvar		7
start loss			2 clinvar			2
frameshift			13 clinvar			13
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	3	3	233	127	29	395

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 86 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006164.5	RefSeq	NP_006155.2	5	MANE Select
ENST00000397062.8	Ensembl	ENSP00000380252.3	5	MANE Select
NM_001145412.3	RefSeq	NP_001138884.1	4	Standard
NM_001145413.3	RefSeq	NP_001138885.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
nfe2l2b	Danio rerio	Structure: anatomical structure Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

nfe2l2b

Danio rerio

Structure: anatomical structure

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Protein processing in endoplasmic reticulum - Homo sapiens (human)
Hepatocellular carcinoma - Homo sapiens (human)
Fluid shear stress and atherosclerosis - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)
Quercetin and Nf-kB- AP-1 Induced Cell Apoptosis

Biological Process

transcription by RNA polymerase II
inflammatory response
aging
proteasomal ubiquitin-independent protein catabolic process
positive regulation of gene expression

Molecular Function

transcription regulatory region sequence-specific DNA binding
RNA polymerase II distal enhancer sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
RNA polymerase II activating transcription factor binding
transcription cofactor binding

Cellular Component

chromatin
nucleus
nucleoplasm
cytoplasm
Golgi apparatus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000397062
Coding exons: 5
Length: 165103
Individuals with no LoFs: 124778
Homozygous LoFs: 0
Heterozygous LoFs: 14
Defined: 124792
p: 0.0000561

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.21	252	312	0.807	0.0000155	4029
Missense (PolyPhen)		39	83.019	0.46977		1101
Synonymous	0.842	105	117	0.901	0.00000611	1134
Loss of Function	2.74	8	21.8	0.367	0.00000107	284

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00013	0.00012	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00017	0.00017	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000037	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription activator that binds to antioxidant response (ARE) elements in the promoter regions of target genes. Important for the coordinated up-regulation of genes in response to oxidative stress and the regulation of cellular redox conditions. May be involved in the transcriptional activation of genes of the beta-globin cluster by mediating enhancer activity of hypersensitive site 2 of the beta-globin locus control region. {ECO:0000269|PubMed:11035812, ECO:0000269|PubMed:29018201}.;
Disease: DISEASE: Immunodeficiency, developmental delay, and hypohomocysteinemia (IMDDHH) [MIM:617744]: An early onset multisystem disorder characterized by immunodeficiency, recurrent infections, developmental delay, poor growth, intellectual disability, and hypohomocysteinemia. Some patients manifest congenital cardiac defects. IMDDHH inheritance pattern is autosomal dominant. {ECO:0000269|PubMed:29018201}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.101

Intolerance Scores

LoFtool: 0.199
RVIS EVS: 0.04
RVIS percentile EVS: 57.31

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.993

Gene Damage Prediction

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