GeneBe

NCF4

protein-coding

neutrophil cytosolic factor 4

Gene 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 interacts primarily with neutrophil cytosolic factor 2 (NCF2/p67-phox) to form a complex with neutrophil cytosolic factor 1 (NCF1/p47-phox), which further interacts with the small G protein RAC1 and translocates to the membrane upon cell stimulation. This complex then activates flavocytochrome b, the membrane-integrated catalytic core of the enzyme system. The PX domain of this protein can bind phospholipid products of the PI(3) kinase, which suggests its role in PI(3) kinase-mediated signaling events. The phosphorylation of this protein was found to negatively regulate the enzyme activity. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000631.5

Inheritance

AR

ClinVar variants

P:23U:132B:95

Top phenotype

Granulomatous disease, chronic, autosomal recessive, 3

gnomAD constraint

pLI —, LoF o/e 0.75

Max pathogenic AF

—

Genomic locus

chr22:36,860,988-36,878,017

External References & Databases

Ensembl (ENSG00000100365)NCBI Gene (4689)OMIM (601488)HGNC:7662GenCCUniProt (Q15080)AlphaFoldClinVar (NCF4)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~17.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013507

Submitter: PanelApp Australia

chronic granulomatous diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018305

Submitter: Orphanet

granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013507

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Granulomatous disease, chronic, autosomal recessive, 3AR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Surveillance for infections and infectious complications is indicatred, and preventive measures (eg, antibacterial/antifungal prophylaxis, interferon gamma) may be beneficial; To treat fungal infections, specific antifungal drugs may be beneficial, and longer treatment courses (as well as specific considerations including coadministration with corticosteroids) may be indicated in individuals with CGD; In some instances, HSCT may be beneficial; Certain agents should be avoided, including material that would allow fungal spore inhalation

Refs: 19692703; 22157170; 22876374Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NCF4 variants in ClinVar

6 Conditions Cataloged
Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3Total: 354
not specifiedTotal: 120
not providedTotal: 60
NCF4-related disorderTotal: 15
Chronic granulomatous diseaseTotal: 6
Primary immunodeficiency or monogenic inflammatory bowel diseaseTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000631.5. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
4
clinvar
79
clinvar
3
clinvar
 87
missense
1
clinvar
124
clinvar
13
clinvar
 138
nonsense
2
clinvar
1
clinvar
 3
start loss
2
clinvar
 2
frameshift
5
clinvar
3
clinvar
 8
splice donor/acceptor (+/-2bp)
1
clinvar
8
clinvar
3
clinvar
 12
Total1013132923250

Highest pathogenic variant AF is 0.00016110323

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000631.5RefSeqNP_000622.210MANE Select
ENST00000248899.11EnsemblENSP00000248899.610MANE Select
NM_013416.4RefSeqNP_038202.28Standard
ENST00000397147.7EnsemblENSP00000380334.48Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Phagosome - Homo sapiens (human)
  • Doxorubicin Pathway (Cardiomyocyte Cell), Pharmacodynamics
  • Leishmaniasis - Homo sapiens (human)
  • Osteoclast differentiation - Homo sapiens (human)
  • Leukocyte transendothelial migration - Homo sapiens (human)

Biological Process

  • superoxide metabolic process
  • phagocytosis
  • immune response
  • positive regulation of catalytic activity
  • respiratory burst

Molecular Function

  • protein binding
  • superoxide-generating NADPH oxidase activator activity
  • phosphatidylinositol-3-phosphate binding
  • phosphatidylinositol binding
  • protein dimerization activity

Cellular Component

  • cytosol
  • endosome membrane
  • membrane
  • phagolysosome
  • NADPH oxidase complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000397147
Coding exons
8
Length
17028
Individuals with no LoFs
125613
Homozygous LoFs
1
Heterozygous LoFs
134
Defined
125748
p
0.000537
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.2272152061.040.00001432247
Missense (PolyPhen)6160.581.0069621
Synonymous-1.4110083.61.200.00000560710
Loss of Function0.9491317.30.7548.54e-7193

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000250.00025rare
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish0.000690.00069rare
East Asian0.000220.00022rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.000760.00075rare
South Asian0.000910.00091rare
Other0.000810.00081rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Component of the NADPH-oxidase, a multicomponent enzyme system responsible for the oxidative burst in which electrons are transported from NADPH to molecular oxygen, generating reactive oxidant intermediates. It may be important for the assembly and/or activation of the NADPH-oxidase complex. {ECO:0000269|PubMed:8280052}.;
Disease
DISEASE: Granulomatous disease, chronic, cytochrome-b-positive 3, autosomal recessive (CGD3) [MIM:613960]: A disorder characterized by the inability of neutrophils and phagocytes to kill microbes that they have ingested. Patients suffer from life-threatening bacterial/fungal infections. {ECO:0000269|PubMed:19692703}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool
0.855
RVIS EVS
-0.78
RVIS percentile EVS
12.97

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.806

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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