NOX4

protein-coding

NADPH oxidase 4

Gene summary

This gene encodes a member of the NOX-family of enzymes that functions as the catalytic subunit the NADPH oxidase complex. The encoded protein is localized to non-phagocytic cells where it acts as an oxygen sensor and catalyzes the reduction of molecular oxygen to various reactive oxygen species (ROS). The ROS generated by this protein have been implicated in numerous biological functions including signal transduction, cell differentiation and tumor cell growth. A pseudogene has been identified on the other arm of chromosome 11. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jan 2009]

MANE transcript

NM_016931.5

Inheritance

—

ClinVar variants

U:81B:7

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.85

Max pathogenic AF

—

Genomic locus

chr11:89,324,353-89,498,187

External References & Databases

Ensembl (ENSG00000086991)

Transcript & Mutation Effects

hg38 • Region Span ~173.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NOX4 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 75

not providedTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016931.5. 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				2 clinvar	1 clinvar	3
missense			77 clinvar	3 clinvar	1 clinvar	81
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	0	0	81	5	2	88

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016931.5	RefSeq	NP_058627.2	18	MANE Select
ENST00000263317.9	Ensembl	ENSP00000263317.4	18	MANE Select
NM_001143836.3	RefSeq	NP_001137308.2	17	Standard
NM_001143837.2	RefSeq	NP_001137309.2	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)
Thyroid hormone synthesis
Angiogenesis overview
Spinal Cord Injury
Oxidative Stress

Biological Process

cell morphogenesis
response to hypoxia
heart process
superoxide metabolic process
defense response

Molecular Function

nucleotide binding
protein binding
electron transfer activity
NAD(P)H oxidase activity
superoxide-generating NADPH oxidase activity

Cellular Component

stress fiber
nucleus
nucleolus
mitochondrion
endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000263317
Coding exons: 18
Length: 265256
Individuals with no LoFs: 125663
Homozygous LoFs: 0
Heterozygous LoFs: 85
Defined: 125748
p: 0.000338

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.898	340	296	1.15	0.0000144	3759
Missense (PolyPhen)		94	97.019	0.96889		1252
Synonymous	-3.37	151	107	1.41	0.00000516	1067
Loss of Function	0.857	33	38.8	0.851	0.00000213	446

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00072	0.00068	rare
Latino/Admixed American	0.00025	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00040	0.00038	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00020	0.00019	rare
South Asian	0.0011	0.0011	notable
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Constitutive NADPH oxidase which generates superoxide intracellularly upon formation of a complex with CYBA/p22phox. Regulates signaling cascades probably through phosphatases inhibition. May function as an oxygen sensor regulating the KCNK3/TASK-1 potassium channel and HIF1A activity. May regulate insulin signaling cascade. May play a role in apoptosis, bone resorption and lipolysaccharide-mediated activation of NFKB. May produce superoxide in the nucleus and play a role in regulating gene expression upon cell stimulation. Isoform 3 is not functional. Isoform 5 and isoform 6 display reduced activity.;

Recessive Scores

pRec: 0.330

Intolerance Scores

LoFtool: 0.0754
RVIS EVS: 0.11
RVIS percentile EVS: 62.1

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.190

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High