NGF
protein-codingnerve growth factor, the group of Neurotrophins
Gene summary
This gene is a member of the NGF-beta family and encodes a secreted protein which homodimerizes and is incorporated into a larger complex. This protein has nerve growth stimulating activity and the complex is involved in the regulation of growth and the differentiation of sympathetic and certain sensory neurons. Mutations in this gene have been associated with hereditary sensory and autonomic neuropathy, type 5 (HSAN5), and dysregulation of this gene's expression is associated with allergic rhinitis. [provided by RefSeq, Jul 2008]
- NGFB
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~52.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0015364
Submitter: ClinGen
NGF was first reported in relation to autosomal recessive hereditary sensory and autonomic neuropathy in 2004 (Einarsdottir et al., PMID: 14976160). The associated relationship is with hereditary sensory and autonomic neuropathy (MONDO:0015364). Three variants (missense and stop-gained) have been reported in 4 probands in 4 publications (PMIDs: 14976160, 20978020, 30296891, 33884296) are included in this curation. The score for genetic evidence was 9.4 with a summed LOD score of 4.98. The mechanism of pathogenicity appears to be a loss-of-function given the functional alteration showing an inability to activate TRKA (PMID: 20978020). Knock-in murine models show reduced thermal sensation, reduced chemical nociception, and non-myelinated fibers (PMID: 32693191, 31685654). In summary, NGF is STRONGLY associated with autosomal recessive hereditary and autonomic neuropathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0012092
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012092
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0012092
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0012092
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
Comments: Insensivity to pain may result in injuries and infections
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NGF variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002506.3. 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 | 60 | 1 | 62 | ||
| missense | 1 | 106 | 8 | 115 | ||
| nonsense | 1 | 1 | 2 | |||
| start loss | 0 | |||||
| frameshift | 1 | 2 | 3 | |||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 2 | 1 | 111 | 68 | 1 | 183 |
Highest pathogenic variant AF is 0.000005578579
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002497.2 | 1 | MANE Select | |
| Ensembl | ENSP00000358525.2 | 1 | MANE Select | |
| RefSeq | NP_001424474.1 | 1 | Standard | |
| Ensembl | ENSP00000502831.1 | 1 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- Inflammatory mediator regulation of TRP channels - Homo sapiens (human)
- Neurotrophin signaling pathway - Homo sapiens (human)
- Rap1 signaling pathway - Homo sapiens (human)
- Ras signaling pathway - Homo sapiens (human)
Biological Process
- activation of MAPKK activity
- activation of cysteine-type endopeptidase activity involved in apoptotic process
- transmembrane receptor protein tyrosine kinase signaling pathway
- peripheral nervous system development
- memory
Molecular Function
- nerve growth factor receptor binding
- protein binding
- growth factor activity
- metalloendopeptidase inhibitor activity
Cellular Component
- extracellular region
- extracellular space
- Golgi lumen
- cytosol
- synaptic vesicle
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000369512
- Coding exons
- 1
- Length
- 52319
- Individuals with no LoFs
- 125745
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 125748
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.903 | 127 | 159 | 0.798 | 0.0000109 | 1584 |
| Missense (PolyPhen) | 45 | 69.225 | 0.65006 | 655 | ||
| Synonymous | -1.06 | 74 | 63.3 | 1.17 | 0.00000430 | 508 |
| Loss of Function | 2.21 | 0 | 5.67 | 0.00 | 3.27e-7 | 63 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Nerve growth factor is important for the development and maintenance of the sympathetic and sensory nervous systems. Extracellular ligand for the NTRK1 and NGFR receptors, activates cellular signaling cascades through those receptor tyrosine kinase to regulate neuronal proliferation, differentiation and survival. Inhibits metalloproteinase dependent proteolysis of platelet glycoprotein VI (PubMed:20164177). {ECO:0000269|PubMed:20164177}.;
- Disease
- DISEASE: Neuropathy, hereditary sensory and autonomic, 5 (HSAN5) [MIM:608654]: A form of hereditary sensory and autonomic neuropathy, a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by sensory and/or autonomic abnormalities. HSAN5 patients manifest loss of pain perception and impaired temperature sensitivity, ulcers, and in some cases self- mutilation. The autonomic involvement is variable. {ECO:0000269|PubMed:14976160, ECO:0000269|PubMed:20978020, ECO:0000269|PubMed:22302274}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.956
Intolerance Scores
- LoFtool
- 0.0944
- RVIS EVS
- 0.11
- RVIS percentile EVS
- 61.73
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.693
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |