MET
protein-codingMET proto-oncogene, receptor tyrosine kinase, the group of Receptor tyrosine kinases|IPT domain containing
Gene summary
This gene encodes a member of the receptor tyrosine kinase family of proteins and the product of the proto-oncogene MET. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that are linked via disulfide bonds to form the mature receptor. Further processing of the beta subunit results in the formation of the M10 peptide, which has been shown to reduce lung fibrosis. Binding of its ligand, hepatocyte growth factor, induces dimerization and activation of the receptor, which plays a role in cellular survival, embryogenesis, and cellular migration and invasion. Mutations in this gene are associated with papillary renal cell carcinoma, hepatocellular carcinoma, and various head and neck cancers. Amplification and overexpression of this gene are also associated with multiple human cancers. [provided by RefSeq, May 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~126.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0003789
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0017884
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0017884
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011806
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0031045
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014739
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0019497
Submitter: ClinGen
MET was first reported in relation to autosomal recessive nonsyndromic hearing loss in 2015 (Mujtaba et al., PMID: 25941349). This association was made using case-level data only. Three missense variants that have been reported in 3 probands in 3 publications (PMIDs: 25941349, 27717089, 31801140) are included in this curation. Only one missense variant was scored as the probands with the other variant had inconsistent phenotypes with nonsyndromic hearing loss and the minor allele frequency of the other variant was too high to be considered pathogenic. One missense variant in this gene segregated with disease in 8 additional family members (PMID: 25941349). While no variant-level functional evidence has been published, this gene-disease association is supported by an expression study, a biochemical study consistent with the phenotype, and an animal model (PMID: 27488639). In summary, there is limited evidence to support this gene-disease association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. This classification was approved by the ClinGen Hearing Loss Gene Curation Expert Panel on the meeting date 3/26/2021 (SOP Version 8). This gene-disease pair was originally evaluated by the ClinGen Hearing Loss GCEP on 12/19/2017. It was reevaluated on 3/26/2021. As a result of this reevaluation, the classification did not change.
Inheritance Pattern: AD
Disease ID:MONDO:0003789
Submitter: G2P
Inheritance Pattern: Unknown
Disease ID:MONDO:0031045
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0017884
Submitter: ClinGen
There is abundant published evidence associating the MET gene with papillary renal cell carcinoma since the gene-disease relationship was first proposed by Schmidt et al. (1997). Multiple case level studies have been performed with RCCP patients that have variants in the MET gene. Since gain of function is the disease mechanism, all pathogenic variants reported so far are missense variants. MET expresses in hepatocytes, epithelial cells and kidney. MET mutants exhibit increased levels of tyrosine phosphorylation and enhanced kinase activity in cell assays. Mutant MET molecules form foci in vitro and are tumorigenic in nude mice. Multiple MET knock-in in vivo mouse models of the kinase domain mutations have been established to show consistent phenotypes of tumorigenesis with RCCP patients. All of these types of evidence are consistent with a definitive relationship between the MET gene and papillary renal cell carcinoma.
Inheritance Pattern: AD
Disease ID:MONDO:0017884
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014739
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0003789
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011806
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: ClinGen
The MET gene, which encodes a receptor tyrosine kinase, has been reported in the literature in association with papillary renal cell carcinoma, deafness, and neurodevelopmental disorders (autism spectrum disorder [ASD] and developmental disorders). The relationships between MET and both papillary renal cell carcinoma and nonsyndromic genetic deafness have previously been evaluated by other ClinGen gene curation expert panels; please see those curation summaries for further information. This curation is focused on the relationship between MET and complex neurodevelopmental disorder. The available genetic evidence for MET in the context of neurodevelopmental disorders can be divided into two categories: association studies of common genetic variants and large cohort studies of rare variants. Between 2006 and 2010, several studies suggested that common noncoding variants in MET were associated with autism susceptibility (PMIDs: 17053076, 19002214, 19681062, 20615438). However, these association studies were all extremely underpowered and their findings were not validated in a very large GWAS study in ASD (PMID: 30804558). Four rare de novo missense variants in the MET gene have also been observed in individuals with ASD or developmental disorders (PMIDs: 25533962, 29346770, 28714951). Three of these variants have been observed in multiple individuals in gnomAD v2.1.1. and were therefore not scored. The other missense variant was not present in gnomAD, but in the absence of functional evidence of pathogenicity was also not scored. A fifth case involved a boy with autism, severe language delay, and learning disabilities and an intragenic deletion including exons 12-15 of the MET gene (PMID: 24909855). The proband had two siblings with learning disabilities, language and social impairment, but only one carried the deletion. Further, while this variant was not inherited from the proband’s mother, the father was unavailable for testing or clinical evaluation. Because of this, we opted not to score this variant. The experimental evidence for MET includes expression studies and mouse models, which evaluated different brain subregions, synaptic transmission and behavioral alterations (PMIDs: 7651534, 26523156, 20853516, 21509596, 21490227, 25471559, 26290232). The Met full knockout is lethal (PMID: 7651534), hence, the available mouse models were conditional knockouts for different brain cell types (PMID: 29188052). Met mutant mice showed abnormal dendritic spine morphology (PMIDs: 20853516, 21509596) and hypoactivity across several behavioral tasks (PMID: 26523156). However, sociability and social novelty preference were intact in the mutant animals and there was no evidence for increased anxiety or repetitive behaviors (PMID: 26523156). In the absence of human genetic evidence, this experimental evidence was not scored. Overall, there is currently no convincing evidence to support a relationship between MET and complex neurodevelopmental disorder, so this gene-disease relationship is disputed. The ClinGen Intellectual Disability and Autism Gene Curation Expert Panel approved this classification on 01/19/2021 (SOP Version 8).
Inheritance Pattern: AR
Disease ID:MONDO:0019588
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Musculoskeletal; Oncologic
Intervention: Audiologic/Otolaryngologic; Oncologic
Rationale: In Renal cell carcinoma, papillary, surveillance and/or awareness of cancer risk may yield early detection of neoplasms may allow early treatment, which may reduce morbidity and mortality; In Deafness, autosomal recessive 97, early recognition and treatment of hearing impairment may improve outcomes, including speech and language development
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MET variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000245.4. 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 | 23 | 1108 | 61 | 1192 | ||
| missense | 5 | 9 | 2180 | 641 | 8 | 2843 |
| nonsense | 1 | 60 | 1 | 62 | ||
| start loss | 2 | 2 | ||||
| frameshift | 1 | 76 | 77 | |||
| splice donor/acceptor (+/-2bp) | 53 | 4 | 57 | |||
| Total | 6 | 10 | 2394 | 1754 | 69 | 4233 |
Highest pathogenic variant AF is 0.000007435276
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000236.2 | 20 | MANE Select | |
| Ensembl | ENSP00000380860.3 | 20 | MANE Select | |
| RefSeq | NP_001120972.1 | 20 | Standard | |
| RefSeq | NP_001311330.1 | 11 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| met | Danio rerio | Structure: pancreatic ductal cell Quality: located in abnormal |
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)
- Central carbon metabolism in cancer - Homo sapiens (human)
Biological Process
- MAPK cascade
- endothelial cell morphogenesis
- liver development
- phagocytosis
- signal transduction
Molecular Function
- protein tyrosine kinase activity
- transmembrane receptor protein tyrosine kinase activity
- hepatocyte growth factor-activated receptor activity
- Ras guanyl-nucleotide exchange factor activity
- protein binding
Cellular Component
- extracellular region
- plasma membrane
- integral component of plasma membrane
- basal plasma membrane
- cell surface
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000318493
- Coding exons
- 20
- Length
- 125997
- Individuals with no LoFs
- 124770
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 20
- Defined
- 124790
- p
- 0.0000801
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.92 | 600 | 748 | 0.803 | 0.0000404 | 9280 |
| Missense (PolyPhen) | 224 | 368.42 | 0.60801 | 4681 | ||
| Synonymous | -0.174 | 288 | 284 | 1.01 | 0.0000168 | 2726 |
| Loss of Function | 6.01 | 12 | 63.8 | 0.188 | 0.00000378 | 742 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00013 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000056 | 0.000056 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00013 | 0.00013 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including proliferation, scattering, morphogenesis and survival. Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. The RAS-ERK activation is associated with the morphogenetic effects while PI3K/AKT coordinates prosurvival effects. During embryonic development, MET signaling plays a role in gastrulation, development and migration of muscles and neuronal precursors, angiogenesis and kidney formation. In adults, participates in wound healing as well as organ regeneration and tissue remodeling. Promotes also differentiation and proliferation of hematopoietic cells. May regulate cortical bone osteogenesis (By similarity). {ECO:0000250|UniProtKB:P16056}.;
- Disease
- DISEASE: Note=Activation of MET after rearrangement with the TPR gene produces an oncogenic protein.; DISEASE: Note=Defects in MET may be associated with gastric cancer.; DISEASE: Hepatocellular carcinoma (HCC) [MIM:114550]: A primary malignant neoplasm of epithelial liver cells. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. {ECO:0000269|PubMed:9927037}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Renal cell carcinoma papillary (RCCP) [MIM:605074]: A subtype of renal cell carcinoma tending to show a tubulo-papillary architecture formed by numerous, irregular, finger-like projections of connective tissue. Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. {ECO:0000269|PubMed:10327054, ECO:0000269|PubMed:10417759, ECO:0000269|PubMed:10433944, ECO:0000269|PubMed:9140397, ECO:0000269|PubMed:9563489}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A common allele in the promoter region of the MET shows genetic association with susceptibility to autism in some families. Functional assays indicate a decrease in MET promoter activity and altered binding of specific transcription factor complexes.; DISEASE: Note=MET activating mutations may be involved in the development of a highly malignant, metastatic syndrome known as cancer of unknown primary origin (CUP) or primary occult malignancy. Systemic neoplastic spread is generally a late event in cancer progression. However, in some instances, distant dissemination arises at a very early stage, so that metastases reach clinical relevance before primary lesions. Sometimes, the primary lesions cannot be identified in spite of the progresses in the diagnosis of malignancies.; DISEASE: Deafness, autosomal recessive, 97 (DFNB97) [MIM:616705]: A form of non-syndromic sensorineural hearing loss with prelingual onset. 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:25941349}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Osteofibrous dysplasia (OSFD) [MIM:607278]: A congenital disorder of osteogenesis characterized by non-neoplastic, radiolucent lesions that affect the cortical bone immediately under the periosteum. It usually manifests as a painless swelling or anterior bowing of the long bones, most commonly the tibia and fibula. {ECO:0000269|PubMed:26637977}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Disease-associated variants identified in 4 families cause the deletion of exon 14. This results in the exclusion of an ubiquitination target site within the cytoplasmic domain, hence in protein stabilization. The persistent presence of MET at the cell surface in conditions of ligand-dependent activation retards osteoblastic differentiation. {ECO:0000269|PubMed:26637977}.;
Recessive Scores
- pRec
- 0.530
Intolerance Scores
- LoFtool
- 0.442
- RVIS EVS
- -0.46
- RVIS percentile EVS
- 23.73
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.985
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |