HGF
protein-codinghepatocyte growth factor
Gene summary
This gene encodes a protein that binds to the hepatocyte growth factor receptor to regulate cell growth, cell motility and morphogenesis in numerous cell and tissue types. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate alpha and beta chains, which form the mature heterodimer. This protein is secreted by mesenchymal cells and acts as a multi-functional cytokine on cells of mainly epithelial origin. This protein also plays a role in angiogenesis, tumorogenesis, and tissue regeneration. Although the encoded protein is a member of the peptidase S1 family of serine proteases, it lacks peptidase activity. Mutations in this gene are associated with nonsyndromic hearing loss. [provided by RefSeq, Nov 2015]
- DFNB39
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~71.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0019497
Submitter: ClinGen
*HGF* was first reported in relation to autosomal recessive nonsyndromic hearing loss (AR NSHL) in 2009 (Schultz et al., 19576567). At least three unique variants (silent, deep intronic deletions) that have been reported in 3 probands in one publication are included in this curation (PMID: 19576567). One of the deep intronic deletions is a founder variant in Pakistan and is present in at least 36 families with hearing loss (PMID: 19576567). Variants in this gene also segregated with disease in at least 41 additional individuals in 22 families (PMID: 19576567). The mechanism for disease is likely loss of function. This gene-disease relationship is supported by expression and biochemical function studies, along with at least four mouse models, one of which recapitulates the deafness phenotype with the same 10 bp deletion of *Hgf* in the intron in humans (27488639, 19576567, 32152201). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the ClinGen Hearing Loss GCEP on 1/16/2018 as per SOP v5. It was reevaluated on 5/3/2024 using SOP v10. No new evidence has been reviewed or added. As a result of this reevaluation, the classification did not change.
Inheritance Pattern: AR
Disease ID:MONDO:0012003
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0019297
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0012003
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0012003
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0019588
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012003
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic
Intervention: Audiologic/Otolaryngologic
Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HGF variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000601.6. 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 | 4 | 39 | 2 | 46 | |
| missense | 148 | 6 | 154 | |||
| nonsense | 4 | 1 | 1 | 1 | 7 | |
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | 2 | |||
| Total | 6 | 2 | 154 | 46 | 2 | 210 |
Highest pathogenic variant AF is 0.000006576092
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000592.3 | 18 | MANE Select | |
| Ensembl | ENSP00000222390.5 | 18 | MANE Select | |
| RefSeq | NP_001010931.1 | 8 | Standard | |
| RefSeq | NP_001010932.1 | 18 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- Gastric cancer - Homo sapiens (human)
- Focal adhesion - Homo sapiens (human)
- Renal cell carcinoma - Homo sapiens (human)
- Melanoma - Homo sapiens (human)
Biological Process
- MAPK cascade
- activation of MAPK activity
- mitotic cell cycle
- cell morphogenesis
- epithelial to mesenchymal transition
Molecular Function
- serine-type endopeptidase activity
- protein tyrosine kinase activity
- Ras guanyl-nucleotide exchange factor activity
- protein binding
- growth factor activity
Cellular Component
- extracellular region
- extracellular space
- membrane
- platelet alpha granule lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000222390
- Coding exons
- 18
- Length
- 71433
- Individuals with no LoFs
- 125732
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 14
- Defined
- 125746
- p
- 0.0000557
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.85 | 305 | 410 | 0.744 | 0.0000220 | 4777 |
| Missense (PolyPhen) | 111 | 183.68 | 0.6043 | 2135 | ||
| Synonymous | -0.673 | 145 | 135 | 1.07 | 0.00000703 | 1314 |
| Loss of Function | 5.82 | 7 | 52.6 | 0.133 | 0.00000339 | 537 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000044 | 0.000044 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Potent mitogen for mature parenchymal hepatocyte cells, seems to be a hepatotrophic factor, and acts as a growth factor for a broad spectrum of tissues and cell types. Activating ligand for the receptor tyrosine kinase MET by binding to it and promoting its dimerization. {ECO:0000269|PubMed:15167892, ECO:0000269|PubMed:20624990}.;
- Disease
- DISEASE: Deafness, autosomal recessive, 39 (DFNB39) [MIM:608265]: A form of profound prelingual sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:19576567}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.759
Intolerance Scores
- LoFtool
- 0.131
- RVIS EVS
- -0.42
- RVIS percentile EVS
- 25.64
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.523
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |