NFE2L2

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

Basic information

Region (hg38): 2:177218667-177392756

Links

ENSG00000116044 ∙ NCBI:4780 ∙ OMIM:600492 ∙ HGNC:7782 ∙ Uniprot:Q16236 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• immunodeficiency, developmental delay, and hypohomocysteinemia (Strong), mode of inheritance: AD
• immunodeficiency, developmental delay, and hypohomocysteinemia (Limited), mode of inheritance: AD
• immunodeficiency, developmental delay, and hypohomocysteinemia (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency, developmental delay, and hypohomocysteinemia	AD	Allergy/Immunology/Infectious; Biochemical	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	Allergy/Immunology/Infectious; Biochemical; Cardiovascular; Gastrointestinal; Neurologic	29018201

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NFE2L2 gene.

• not provided (1 variants)
• Immunodeficiency, developmental delay, and hypohomocysteinemia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NFE2L2 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				74	3	77
missense	1		132	9	18	160
nonsense			4	1		5
start loss						0
frameshift			4			4
inframe indel			2			2
splice donor/acceptor (+/-2bp)			2			2
splice region			1	8		9
non coding				10	7	17
Total	1	0	144	94	28

Variants in NFE2L2

This is a list of pathogenic ClinVar variants found in the NFE2L2 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-177219111-A-C		not specified	Uncertain significance (Jun 02, 2024)
2-177230792-T-C			Uncertain significance (Feb 07, 2022)
2-177230794-C-T			Likely benign (Nov 28, 2023)
2-177230801-T-A			Uncertain significance (Sep 10, 2023)
2-177230805-G-C			Benign (Nov 27, 2023)
2-177230818-G-C			Likely benign (Feb 05, 2022)
2-177230834-T-C			Uncertain significance (Dec 09, 2023)
2-177230838-C-T		NFE2L2-related disorder	Uncertain significance (Jan 06, 2023)
2-177230871-G-T		NFE2L2-related disorder	Uncertain significance (Aug 23, 2024)
2-177230875-A-G			Likely benign (Dec 11, 2023)
2-177230877-A-G			Uncertain significance (Jun 27, 2023)
2-177230887-A-G			Likely benign (Sep 01, 2022)
2-177230893-A-G			Likely benign (Jan 17, 2024)
2-177230897-C-T			Uncertain significance (Jan 18, 2024)
2-177230898-G-A		not specified	Uncertain significance (Jul 26, 2023)
2-177230907-T-C			Uncertain significance (Apr 14, 2023)
2-177230913-C-T			Uncertain significance (Dec 08, 2023)
2-177230917-G-A			Likely benign (Jan 16, 2023)
2-177230917-G-C			Likely benign (Apr 10, 2023)
2-177230918-A-C		NFE2L2-related disorder	Uncertain significance (Jan 06, 2024)
2-177230923-T-A			Uncertain significance (Aug 30, 2023)
2-177230923-T-C			Likely benign (Oct 24, 2023)
2-177230935-T-C			Likely benign (Jul 26, 2022)
2-177230936-T-C			Uncertain significance (Apr 09, 2023)
2-177230937-G-T			Uncertain significance (Jul 02, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NFE2L2	protein_coding	protein_coding	ENST00000397062	5	165103

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00357	0.995	124778	0	14	124792	0.0000561

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.21	252	312	0.807	0.0000155	4029
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000125	0.000125
Ashkenazi Jewish	0.0000993	0.0000993
East Asian	0.000168	0.000167
Finnish	0.00	0.00
European (Non-Finnish)	0.0000443	0.0000441
Middle Eastern	0.000168	0.000167
South Asian	0.0000369	0.0000327
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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;Aryl Hydrocarbon Receptor;Selenium Metabolism and Selenoproteins;Mesodermal Commitment Pathway;Aryl Hydrocarbon Receptor Pathway;Nuclear Receptors Meta-Pathway;NRF2 pathway;Transcriptional activation by NRF2;Photodynamic therapy-induced AP-1 survival signaling.;Photodynamic therapy-induced NFE2L2 (NRF2) survival signaling;Photodynamic therapy-induced unfolded protein response;Lung fibrosis;Simplified Interaction Map Between LOXL4 and Oxidative Stress Pathway;Oxidative Stress;Hereditary Leiomyomatosis and Renal Cell Carcinoma Pathway;oxidative stress induced gene expression via nrf2 (Consensus)

Recessive Scores

• pRec: 0.101

Intolerance Scores

• loftool: 0.199
• rvis_EVS: 0.04
• rvis_percentile_EVS: 57.31

Haploinsufficiency Scores

• pHI: 0.547
• hipred: Y
• hipred_score: 0.825
• ghis: 0.494

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.993

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nfe2l2
• Phenotype: embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; liver/biliary system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system 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); normal phenotype; neoplasm; digestive/alimentary 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); immune system phenotype; cellular phenotype; renal/urinary system phenotype; skeleton phenotype; growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); craniofacial phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: nfe2l2b
• Affected structure: anatomical structure
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: transcription by RNA polymerase II;inflammatory response;aging;proteasomal ubiquitin-independent protein catabolic process;positive regulation of gene expression;negative regulation of cardiac muscle cell apoptotic process;positive regulation of neuron projection development;viral process;protein ubiquitination;positive regulation of blood coagulation;endoplasmic reticulum unfolded protein response;cellular response to oxidative stress;positive regulation of transcription from RNA polymerase II promoter in response to stress;positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress;PERK-mediated unfolded protein response;cellular response to glucose starvation;proteasome-mediated ubiquitin-dependent protein catabolic process;positive regulation of blood vessel endothelial cell migration;cell redox homeostasis;positive regulation of angiogenesis;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;regulation of embryonic development;aflatoxin catabolic process;positive regulation of glucose import;positive regulation of transcription from RNA polymerase II promoter in response to hypoxia;cellular response to hydrogen peroxide;cellular response to tumor necrosis factor;cellular response to fluid shear stress;cellular response to laminar fluid shear stress;negative regulation of hematopoietic stem cell differentiation;negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway;positive regulation of ER-associated ubiquitin-dependent protein catabolic process;negative regulation of hydrogen peroxide-induced cell death;positive regulation of glutathione biosynthetic process;cellular response to angiotensin;negative regulation of vascular associated smooth muscle cell migration;regulation of removal of superoxide radicals;negative regulation of endothelial cell apoptotic process;positive regulation of reactive oxygen species metabolic process
• Cellular component: chromatin;nucleus;nucleoplasm;cytoplasm;Golgi apparatus;centrosome;cytosol;plasma membrane;protein-DNA complex
• 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;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA binding;DNA-binding transcription factor activity;protein binding;protein domain specific binding;transcription regulatory region DNA binding