NCF4 (neutrophil cytosolic factor 4)

Gene

• Entrez ID: 4689
• Gene name: Neutrophil cytosolic factor 4
• Gene symbol: NCF4
• Synonyms (NCBI Gene): CGD3, NCF, P40PHOX, SH3PXD4
• Chromosome: 22
• Chromosome location: 22q12.3
• Summary: The protein encoded by this gene is a cytosolic regulatory component of the superoxide-producing phagocyte NADPH-oxidase, a multicomponent enzyme system important for host defense. This protein is preferentially expressed in cells of myeloid lineage. It i

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs201021542	C>T	Pathogenic	Coding sequence variant, stop gained, intron variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT017337	hsa-miR-335-5p	Microarray	18185580
MIRT1176354	hsa-miR-3160-3p	CLIP-seq
MIRT1176355	hsa-miR-3921	CLIP-seq
MIRT1176356	hsa-miR-4251	CLIP-seq
MIRT1176357	hsa-miR-4279	CLIP-seq
MIRT1176358	hsa-miR-4329	CLIP-seq
MIRT1176359	hsa-miR-4653-5p	CLIP-seq
MIRT1176360	hsa-miR-493	CLIP-seq

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0005515	Function	Protein binding	IPI	8280052, 9365277, 11483497, 12887891, 15657040, 16297854, 16782902, 17803994
GO:0005737	Component	Cytoplasm	IBA
GO:0005737	Component	Cytoplasm	IEA
GO:0005768	Component	Endosome	IEA
GO:0005829	Component	Cytosol	IDA	8280052
GO:0005829	Component	Cytosol	IEA
GO:0005829	Component	Cytosol	TAS
GO:0005886	Component	Plasma membrane	NAS	27048830
GO:0006909	Process	Phagocytosis	IEA
GO:0008289	Function	Lipid binding	IEA
GO:0010008	Component	Endosome membrane	IDA	11684018
GO:0010008	Component	Endosome membrane	IEA
GO:0016020	Component	Membrane	IDA	8280052
GO:0016020	Component	Membrane	IEA
GO:0016176	Function	Superoxide-generating NADPH oxidase activator activity	IBA
GO:0016176	Function	Superoxide-generating NADPH oxidase activator activity	IEA
GO:0016176	Function	Superoxide-generating NADPH oxidase activator activity	IMP	8280052
GO:0032010	Component	Phagolysosome	TAS
GO:0032266	Function	Phosphatidylinositol-3-phosphate binding	IDA	11684018
GO:0035091	Function	Phosphatidylinositol binding	IEA
GO:0042554	Process	Superoxide anion generation	IBA
GO:0042554	Process	Superoxide anion generation	IDA	38355798
GO:0042554	Process	Superoxide anion generation	IMP	8280052
GO:0043020	Component	NADPH oxidase complex	IBA
GO:0043020	Component	NADPH oxidase complex	IDA	8280052, 38355798
GO:0043020	Component	NADPH oxidase complex	IEA
GO:0043020	Component	NADPH oxidase complex	NAS	24598074
GO:0045730	Process	Respiratory burst	IEA
GO:0045730	Process	Respiratory burst	NAS	27048830

Other IDs

• MIM: 601488
• HGNC: 7662
• e!Ensembl: ENSG00000100365

Protein

• UniProt ID: Q15080
• Protein name: Neutrophil cytosol factor 4 (NCF-4) (Neutrophil NADPH oxidase factor 4) (SH3 and PX domain-containing protein 4) (p40-phox) (p40phox)
• Protein function: Subunit of the phagocyte NADPH oxidase complex that mediates the transfer of electrons from cytosolic NADPH to O2 to produce the superoxide anion (O2(-)) (Probable). In the activated complex, electrons are first transferred from NADPH to flavin
• PDB: 1H6H, 1OEY, 1W6X, 1W70, 1Z9Q, 2DYB
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00787	PX	45 → 136	PX domain	Domain
  PF00018	SH3_1	176 → 221	SH3 domain	Domain
  PF00564	PB1	237 → 329	PB1 domain	Domain

• Tissue specificity: TISSUE SPECIFICITY: Expression is restricted to hematopoietic cells.
• Sequence:

  MAVAQQLRAESDFEQLPDDVAISANIADIEEKRGFTSHFVFVIEVKTKGGSKYLIYRRYR
  QFHALQSKLEERFGPDSKSSALACTLPTLPAKVYVGVKQEIAEMRIPALNAYMKSLLSLP
  VWVLMDEDVRIFFYQSPYDSEQVPQALRRLRPRTRKVKSVSPQGNSVDRMAAPRAEALFD
  FTGNSKLELNFKAGDVIFLLSRINKDWLEGTVRGATGIFPLSFVKILKDFPEEDDPTNWL
  RCYYYEDTISTIKDIAVEEDLSSTPLLKDLLELTRREFQREDIALNYRDAEGDLVRLLSD
  EDVALMVRQARGLPSQKRLFPWKLHITQKDNYRVYNTMP

• Sequence length: 339

Pathways

KEGG:

Phagosome
Osteoclast differentiation
Neutrophil extracellular trap formation
Leukocyte transendothelial migration
Prion disease
Leishmaniasis
Diabetic cardiomyopathy
Lipid and atherosclerosis

Reactome:

ROS and RNS production in phagocytes
Cross-presentation of particulate exogenous antigens (phagosomes)
Detoxification of Reactive Oxygen Species
VEGFA-VEGFR2 Pathway
RHO GTPases Activate NADPH Oxidases

Associated diseases

Evidence Score:

• ★☆☆☆☆  Gene-disease association found in Text Mining only
• ★★☆☆☆  Found in Text Mining and Unknown/Other Associations
• ★★★☆☆  Reported in Unknown/Other Associations across ≥2 Sources
• ★★★★☆  ClinVar: Pathogenic/Likely Pathogenic (<5 Variants)
• ★★★★★  ClinVar: Pathogenic/Likely Pathogenic (≥5 Variants)

Causal
Phenotype Name	Clinical Significance	dbSNP ID	RCV Accession	Evidence Score
Chronic granulomatous disease	Likely pathogenic; Pathogenic	rs2145702588, rs869025585, rs1940184559, rs867575163, rs387906808, rs201021542	RCV001553596 RCV000208597 RCV005240697 RCV003231038 RCV000208606 RCV005414268	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3	Likely pathogenic; Pathogenic	rs199890705, rs1327793505, rs758210984, rs2517929064, rs869025585, rs1940184559, rs757106743, rs2517929080, rs2517920041, rs2548810898, rs2517929586, rs876657377, rs387906808, rs28445840, rs201021542, rs1200078508, rs1939893821, rs1940176752, rs1601543670	RCV001782503 RCV002635897 RCV002806025 RCV003005028 RCV003525880 RCV003525360 RCV003338085 RCV003525501 RCV003526415 RCV003641646 RCV003641744 RCV000023112 RCV000023113 RCV001200053 RCV000808400 RCV000990433 RCV001045494 RCV001200054 RCV001200055	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)

Unknown / Other Associations
Phenotype Name	Clinical Significance	Source	Evidence Score
Acute myeloid leukemia	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
ASTHMA	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
ATOPIC ECZEMA	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Cervical cancer	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Colon adenocarcinoma	-	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
CROHN DISEASE	—	CTD	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
CROHN'S DISEASE	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
CROHNS DISEASE OF LARGE BOWEL	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Familial cancer of breast	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Gastric cancer	Likely benign; Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, 3	—	CTD, Disgenet, HPO CTD, Disgenet, HPO CTD, Disgenet, HPO	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
HEART DISEASES	—	CTD, Disgenet CTD, Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Hepatocellular carcinoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
INFLAMMATORY BOWEL DISEASE	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Malignant tumor of esophagus	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
MULTIPLE SCLEROSIS	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
NCF4-related disorder	Likely benign; Benign; Uncertain significance; Conflicting classifications of pathogenicity	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Ovarian serous cystadenocarcinoma	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
RESPIRATORY SYSTEM DISEASE	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
RHEUMATOID ARTHRITIS	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Sarcoma	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
ULCERATIVE COLITIS	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Uterine corpus endometrial carcinoma	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations

Associations from Text Mining
Disease Name	Disease (Merged)	Source	PMID	Relationship Type	Evidence Score
Arthritis Rheumatoid	Rheumatoid arthritis	Pubtator	17897462, 33145364	Associate	★☆☆☆☆ Found in Text Mining only
Autoimmune Diseases	Autoimmune Diseases	BEFREE	17897462		★☆☆☆☆ Found in Text Mining only
Autoimmune Diseases	Autoimmune disease	Pubtator	34708124	Associate	★☆☆☆☆ Found in Text Mining only
Carcinoma Renal Cell	Renal cell carcinoma	Pubtator	34708124, 34872567	Associate	★☆☆☆☆ Found in Text Mining only
Cerebral Infarction	Ischemic stroke	Pubtator	32746852	Associate	★☆☆☆☆ Found in Text Mining only
Chronic granulomatous disease	Granulomatous Disease	BEFREE	10672014, 19692703, 20167518, 23826567, 23910690, 26210446, 27222152, 27666509, 29969437, 30319683, 30506560, 8280052		★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Chronic granulomatous disease	Granulomatous Disease	CLINVAR_DG	19692703		★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Chronic granulomatous disease	Granulomatous Disease	Orphanet			★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Chronic Obstructive Airway Disease	Chronic Obstructive Pulmonary Disease	HPO_DG			★☆☆☆☆ Found in Text Mining only
Colitis	Colitis	HPO_DG			★☆☆☆☆ Found in Text Mining only
Colorectal Carcinoma	Colorectal Cancer	BEFREE	23982929		★☆☆☆☆ Found in Text Mining only
Colorectal Neoplasms	Colorectal neoplasm	Pubtator	23982929	Associate	★☆☆☆☆ Found in Text Mining only
Crohn Disease	Crohn Disease	CTD_human_DG	17435756		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Crohn Disease	Crohn Disease	BEFREE	18580884, 19262523, 21122541, 21472827, 21900546		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Crohn Disease	Crohn Disease	LHGDN	18580884		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Crohn Disease	Crohn disease	Pubtator	19692703, 21900546, 29454792, 31027832	Associate	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Crohn Disease	Crohn Disease	GWASCAT_DG	28067908		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Crohn`s disease of large bowel	Crohn`s Disease Of Large Bowel	CTD_human_DG	17435756		★☆☆☆☆ Found in Text Mining only
Crohn`s disease of the ileum	Crohn`s Disease Of The Ileum	CTD_human_DG	17435756		★☆☆☆☆ Found in Text Mining only
Cystic Fibrosis	Cystic Fibrosis	BEFREE	27484450		★☆☆☆☆ Found in Text Mining only
Eczema	Eczema	HPO_DG			★☆☆☆☆ Found in Text Mining only
Eye Diseases	Eye disease	Pubtator	2183623	Associate	★☆☆☆☆ Found in Text Mining only
Gingivitis	Gingivitis	HPO_DG			★☆☆☆☆ Found in Text Mining only
Granulomatous Disease Chronic	Granulomatous disease	Pubtator	19692703, 22924696, 30506560, 30924925, 33746979, 8280052	Associate	★☆☆☆☆ Found in Text Mining only
GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, CYTOCHROME b-POSITIVE, TYPE III	Granulomatous Disease	GENOMICS_ENGLAND_DG	17435756, 29969437		★☆☆☆☆ Found in Text Mining only
GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, CYTOCHROME b-POSITIVE, TYPE III	Granulomatous Disease	UNIPROT_DG	19692703		★☆☆☆☆ Found in Text Mining only
GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, CYTOCHROME b-POSITIVE, TYPE III	Granulomatous Disease	CTD_human_DG			★☆☆☆☆ Found in Text Mining only
Granulomatous Disease, Chronic, X-Linked	Granulomatous Disease	BEFREE	14688376, 30506560		★☆☆☆☆ Found in Text Mining only
Heart Diseases	Heart Diseases	CTD_human_DG	16330681		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Heart Diseases	Heart disease	Pubtator	23576480	Associate	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Hematologic Diseases	Hematologic disease	Pubtator	37058477	Associate	★☆☆☆☆ Found in Text Mining only
IIeocolitis	Ileocolitis	CTD_human_DG	17435756		★☆☆☆☆ Found in Text Mining only
Immune System Diseases	Immune System Diseases	BEFREE	26210446		★☆☆☆☆ Found in Text Mining only
Inflammatory abnormality of the eye	Inflammatory abnormality of the eye	HPO_DG			★☆☆☆☆ Found in Text Mining only
Inflammatory Bowel Diseases	Inflammatory Bowel Disease	BEFREE	18580884, 26289093		★☆☆☆☆ Found in Text Mining only
Inflammatory Bowel Diseases	Inflammatory bowel disease	Pubtator	29228965, 39273699	Associate	★☆☆☆☆ Found in Text Mining only
Latent Autoimmune Diabetes in Adults	Latent autoimmune diabetes in adults	Pubtator	33391182	Associate	★☆☆☆☆ Found in Text Mining only
Lymphoma, Large-Cell, Follicular	Lymphoma	BEFREE	24633940		★☆☆☆☆ Found in Text Mining only
Lymphoma, Non-Hodgkin	Non-Hodgkin lymphoma	BEFREE	24633940		★☆☆☆☆ Found in Text Mining only
Lymphoma, Non-Hodgkin, Familial	Lymphoma	BEFREE	24633940		★☆☆☆☆ Found in Text Mining only
Malabsorption Syndrome	Malabsorption Syndrome	HPO_DG			★☆☆☆☆ Found in Text Mining only
Malignant Neoplasms	Malignant Neoplasm	BEFREE	28068367		★☆☆☆☆ Found in Text Mining only
Mediastinal lymphadenopathy	Mediastinal lymphadenopathy	HPO_DG			★☆☆☆☆ Found in Text Mining only
Necrosis	Necrosis	Pubtator	23576480	Associate	★☆☆☆☆ Found in Text Mining only
NON RARE IN EUROPE: Crohn disease	Crohn disease	Orphanet			★☆☆☆☆ Found in Text Mining only
Otitis Media	Otitis media	HPO_DG			★☆☆☆☆ Found in Text Mining only
Perioral eczema	Perioral eczema	HPO_DG			★☆☆☆☆ Found in Text Mining only
Peroxisome Biogenesis Disorder, Complementation Group D	Zellweger Syndrome	BEFREE	30506560		★☆☆☆☆ Found in Text Mining only
Recurrent aphthous ulcer	Aphthous Ulcer	HPO_DG			★☆☆☆☆ Found in Text Mining only
Recurrent sinusitis	Sinusitis	HPO_DG			★☆☆☆☆ Found in Text Mining only
Regional enteritis	Crohn Disease	CTD_human_DG	17435756		★☆☆☆☆ Found in Text Mining only
Rheumatoid Arthritis	Rheumatoid arthritis	BEFREE	17897462		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Rheumatoid Arthritis	Rheumatoid arthritis	LHGDN	17897462		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Sinusitis	Sinusitis	HPO_DG			★☆☆☆☆ Found in Text Mining only
Spondylitis Ankylosing	Ankylosing spondylitis	Pubtator	37654221	Associate	★☆☆☆☆ Found in Text Mining only
Williams Syndrome	Williams Syndrome	BEFREE	30319683		★☆☆☆☆ Found in Text Mining only