MET

MET proto-oncogene, receptor tyrosine kinase, the group of Receptor tyrosine kinases|IPT domain containing

Basic information

Region (hg38): 7:116672195-116798377

Links

ENSG00000105976 ∙ ∙ OMIM:164860 ∙ HGNC:7029 ∙ Uniprot:P08581 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal recessive nonsyndromic hearing loss 97 (Limited), mode of inheritance: AR
• papillary renal cell carcinoma (Strong), mode of inheritance: AD
• hereditary papillary renal cell carcinoma (Definitive), mode of inheritance: AD
• osteofibrous dysplasia (Limited), mode of inheritance: AD
• papillary renal cell carcinoma (Supportive), mode of inheritance: AD
• hearing loss, autosomal recessive (Supportive), mode of inheritance: AR
• osteofibrous dysplasia (Supportive), mode of inheritance: AD
• autosomal recessive nonsyndromic hearing loss 97 (Limited), mode of inheritance: AR
• arthrogryposis, distal, IIa 11 (Limited), mode of inheritance: AD
• hereditary papillary renal cell carcinoma (Definitive), mode of inheritance: AD
• arthrogryposis, distal, IIa 11 (Limited), mode of inheritance: Unknown
• autosomal recessive nonsyndromic hearing loss 97 (Strong), mode of inheritance: AR
• hereditary papillary renal cell carcinoma (Strong), mode of inheritance: AD
• papillary renal cell carcinoma (Definitive), mode of inheritance: AD
• complex neurodevelopmental disorder (Disputed Evidence), mode of inheritance: AD
• nonsyndromic genetic hearing loss (Limited), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Renal cell carcinoma, papillary; Deafness, autosomal recessive 97	AD/AR	Audiologic/Otolaryngologic; Oncologic	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	Audiologic/Otolaryngologic; Musculoskeletal; Oncologic	1270474; 9140397; 9234973; 9563489; 9731534; 19402075; 22717761; 25941349; 26637977; 30777867

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MET gene.

• Renal cell carcinoma (2426 variants)
• Hereditary cancer-predisposing syndrome (1759 variants)
• not provided (412 variants)
• Papillary renal cell carcinoma type 1 (251 variants)
• not specified (199 variants)
• Autosomal recessive nonsyndromic hearing loss 97 (134 variants)
• MET-related condition (19 variants)
• Hereditary cancer (12 variants)
• Ovarian cancer (7 variants)
• Osteofibrous dysplasia (6 variants)
• Carcinoma (5 variants)
• Intellectual disability (4 variants)
• Renal carcinoma (4 variants)
• Neoplasm (4 variants)
• Inborn genetic diseases (3 variants)
• Osteofibrous dysplasia;Papillary renal cell carcinoma type 1;Hepatocellular carcinoma;Autosomal recessive nonsyndromic hearing loss 97 (3 variants)
• Osteofibrous dysplasia;Hepatocellular carcinoma;Papillary renal cell carcinoma type 1;Autosomal recessive nonsyndromic hearing loss 97 (3 variants)
• Hepatocellular carcinoma;Osteofibrous dysplasia;Autosomal recessive nonsyndromic hearing loss 97;Papillary renal cell carcinoma type 1 (3 variants)
• Osteofibrous dysplasia;Autosomal recessive nonsyndromic hearing loss 97;Papillary renal cell carcinoma type 1;Hepatocellular carcinoma (2 variants)
• Arthrogryposis, distal, IIa 11 (2 variants)
• Hepatocellular carcinoma;Papillary renal cell carcinoma type 1;Autosomal recessive nonsyndromic hearing loss 97;Osteofibrous dysplasia (2 variants)
• Papillary renal cell carcinoma type 1;Hepatocellular carcinoma;Autosomal recessive nonsyndromic hearing loss 97;Osteofibrous dysplasia (2 variants)
• Hepatocellular carcinoma;Autosomal recessive nonsyndromic hearing loss 97;Osteofibrous dysplasia;Papillary renal cell carcinoma type 1 (2 variants)
• Autosomal recessive nonsyndromic hearing loss 97;Hepatocellular carcinoma;Osteofibrous dysplasia;Papillary renal cell carcinoma type 1 (2 variants)
• Hereditary papillary renal cell carcinoma (1 variants)
• Hepatocellular carcinoma;Autosomal recessive nonsyndromic hearing loss 97;Papillary renal cell carcinoma type 1;Osteofibrous dysplasia (1 variants)
• Breast carcinoma (1 variants)
• Lymphedema (1 variants)
• Papillary renal cell carcinoma type 1;Hepatocellular carcinoma;Osteofibrous dysplasia;Autosomal recessive nonsyndromic hearing loss 97 (1 variants)
• Autosomal recessive nonsyndromic hearing loss 97;Osteofibrous dysplasia;Papillary renal cell carcinoma type 1;Hepatocellular carcinoma (1 variants)
• Hepatoblastoma (1 variants)
• Congenital diaphragmatic hernia (1 variants)
• Lung carcinoma (1 variants)
• Osteofibrous dysplasia;Hepatocellular carcinoma;Autosomal recessive nonsyndromic hearing loss 97;Papillary renal cell carcinoma type 1 (1 variants)
• Papillary renal cell carcinoma type 1;Osteofibrous dysplasia;Autosomal recessive nonsyndromic hearing loss 97;Hepatocellular carcinoma (1 variants)
• Nonsyndromic Hearing Loss and Deafness, Autosomal Recessive (1 variants)
• Classic Hodgkin lymphoma (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MET gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			19	768	11	798
missense	4	2	1651	17	2	1676
nonsense			41			41
start loss			1			1
frameshift			30			30
inframe indel			9			9
splice donor/acceptor (+/-2bp)			21	4		25
splice region			57	65	3	125
non coding			59	235	58	352
Total	4	2	1831	1024	71

Highest pathogenic variant AF is 0.00000657

Variants in MET

This is a list of pathogenic ClinVar variants found in the MET region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
7-116672385-C-G		Renal cell carcinoma	Benign (Jan 18, 2024)
7-116672385-C-C		Autism, susceptibility to, 9	Uncertain significance (Nov 07, 2006)
7-116672410-C-A		Papillary renal cell carcinoma type 1	Benign (Jan 13, 2018)
7-116672412-C-A		Papillary renal cell carcinoma type 1	Uncertain significance (Jan 13, 2018)
7-116672427-C-G		Papillary renal cell carcinoma type 1	Uncertain significance (Jan 13, 2018)
7-116672435-T-G		Papillary renal cell carcinoma type 1	Uncertain significance (Jan 12, 2018)
7-116672483-C-T		Papillary renal cell carcinoma type 1	Uncertain significance (Jan 13, 2018)
7-116672511-G-T			Likely benign (Aug 12, 2019)
7-116672526-G-T		Papillary renal cell carcinoma type 1	Uncertain significance (Jan 13, 2018)
7-116672528-G-T		Papillary renal cell carcinoma type 1	Uncertain significance (Jan 12, 2018)
7-116672557-C-G		Papillary renal cell carcinoma type 1	Uncertain significance (Jan 13, 2018)
7-116672813-GA-G			Likely benign (Jun 18, 2018)
7-116695757-A-T		not specified	not provided (Sep 19, 2013)
7-116695774-G-C		not specified	not provided (Sep 19, 2013)
7-116699045-C-T		not specified	Likely benign (Aug 15, 2023)
7-116699058-C-T		Papillary renal cell carcinoma type 1 • not specified	Benign (Aug 15, 2023)
7-116699059-C-G		not specified	Likely benign (Feb 06, 2024)
7-116699067-G-A		not specified • Papillary renal cell carcinoma type 1	Benign/Likely benign (Feb 06, 2024)
7-116699071-ATAAACCTCTCATAATGAAGGCCCCCGCTG-A		Renal cell carcinoma • Hereditary cancer-predisposing syndrome	Uncertain significance (Jan 06, 2021)
7-116699078-T-C		Papillary renal cell carcinoma type 1	Likely benign (Aug 14, 2015)
7-116699082-A-T		Hereditary cancer-predisposing syndrome	Uncertain significance (Apr 07, 2022)
7-116699083-T-C		Hereditary cancer-predisposing syndrome	Uncertain significance (Oct 10, 2023)
7-116699091-G-A		Renal cell carcinoma • Hereditary cancer-predisposing syndrome	Conflicting classifications of pathogenicity (Nov 17, 2023)
7-116699092-C-T		Renal cell carcinoma • Hereditary cancer-predisposing syndrome	Uncertain significance (Mar 01, 2024)
7-116699093-C-T		Renal cell carcinoma • Hereditary cancer-predisposing syndrome	Likely benign (Sep 08, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MET	protein_coding	protein_coding	ENST00000318493	20	125997

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.970	0.0300	124770	0	20	124790	0.0000801

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.92	600	748	0.803	0.0000404	9280
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000132	0.000129
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000556	0.0000556
Finnish	0.00	0.00
European (Non-Finnish)	0.000133	0.000132
Middle Eastern	0.0000556	0.0000556
South Asian	0.0000655	0.0000654
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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}.
• Pathway: 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);Adherens junction - Homo sapiens (human);Melanoma - Homo sapiens (human);Malaria - Homo sapiens (human);Epithelial cell signaling in Helicobacter pylori infection - Homo sapiens (human);Axon guidance - Homo sapiens (human);Hepatocellular carcinoma - Homo sapiens (human);Rap1 signaling pathway - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Bacterial invasion of epithelial cells - Homo sapiens (human);Proteoglycans in cancer - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Transcriptional misregulation in cancer - Homo sapiens (human);Cytokine-cytokine receptor interaction - Homo sapiens (human);miR-targeted genes in epithelium - TarBase;miR-targeted genes in lymphocytes - TarBase;miR-targeted genes in muscle cell - TarBase;miR-targeted genes in squamous cell - TarBase;Signaling Pathways in Glioblastoma;Extracellular vesicle-mediated signaling in recipient cells;Focal Adhesion;Signaling of Hepatocyte Growth Factor Receptor;TGF-beta Signaling Pathway;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;PI3K-Akt Signaling Pathway;MET in type 1 papillary renal cell carcinoma;Ras Signaling;Developmental Biology;Disease;Signal Transduction;MET interacts with TNS proteins;Alpha6Beta4Integrin;HGF;Infectious disease;MET activates RAP1 and RAC1;IL-7 signaling;Sema4D mediated inhibition of cell attachment and migration;EGFR1;MET activates STAT3;Sema4D in semaphorin signaling;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;Signaling events mediated by TCPTP;Semaphorin interactions;PIP3 activates AKT signaling;JAK STAT pathway and regulation;Posttranslational regulation of adherens junction stability and dissassembly;EPO signaling;a6b1 and a6b4 Integrin signaling;PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling;Negative regulation of the PI3K/AKT network;Direct p53 effectors;Axon guidance;Constitutive Signaling by Aberrant PI3K in Cancer;PI3K/AKT Signaling in Cancer;MET Receptor Activation;MET activates RAS signaling;MET activates PI3K/AKT signaling;MET activates PTK2 signaling;MET promotes cell motility;Negative regulation of MET activity;Signaling by MET;Signaling by Receptor Tyrosine Kinases;VEGF;MET activates PTPN11;Intracellular signaling by second messengers;Stabilization and expansion of the E-cadherin adherens junction;Diseases of signal transduction;Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met);Syndecan-1-mediated signaling events;Arf6 signaling events;Regulation of retinoblastoma protein;FGF signaling pathway;InlB-mediated entry of Listeria monocytogenes into host cell;Listeria monocytogenes entry into host cells (Consensus)

Recessive Scores

• pRec: 0.530

Intolerance Scores

• loftool: 0.442
• rvis_EVS: -0.46
• rvis_percentile_EVS: 23.73

Haploinsufficiency Scores

• pHI: 0.753
• hipred: Y
• hipred_score: 0.793
• ghis: 0.543

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.985

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Met
• Phenotype: endocrine/exocrine gland phenotype; growth/size/body region phenotype; craniofacial phenotype; muscle phenotype; cellular phenotype; immune system phenotype; homeostasis/metabolism phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; respiratory system phenotype; embryo phenotype; neoplasm; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; renal/urinary system phenotype

Zebrafish Information Network

• Gene name: met
• Affected structure: pancreatic ductal cell
• Phenotype tag: abnormal
• Phenotype quality: located in

Gene ontology

• Biological process: MAPK cascade;endothelial cell morphogenesis;liver development;phagocytosis;signal transduction;cell surface receptor signaling pathway;transmembrane receptor protein tyrosine kinase signaling pathway;nervous system development;cell population proliferation;negative regulation of autophagy;Wnt signaling pathway;cell migration;peptidyl-tyrosine phosphorylation;neuron differentiation;pancreas development;positive regulation of microtubule polymerization;negative regulation of Rho protein signal transduction;entry of bacterium into host cell;positive regulation of transcription by RNA polymerase II;phosphatidylinositol phosphorylation;hepatocyte growth factor receptor signaling pathway;branching morphogenesis of an epithelial tube;positive chemotaxis;negative regulation of stress fiber assembly;positive regulation of protein kinase B signaling;establishment of skin barrier;negative regulation of thrombin-activated receptor signaling pathway;semaphorin-plexin signaling pathway;negative regulation of hydrogen peroxide-mediated programmed cell death;negative regulation of guanyl-nucleotide exchange factor activity;positive regulation of endothelial cell chemotaxis
• Cellular component: extracellular region;plasma membrane;integral component of plasma membrane;basal plasma membrane;cell surface;integral component of membrane;receptor complex
• 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;ATP binding;Wnt-protein binding;protein phosphatase binding;identical protein binding;phosphatidylinositol-4,5-bisphosphate 3-kinase activity