MET

Chr 7ADAR

MET proto-oncogene, receptor tyrosine kinase

Also known as: AUTS9, DA11, DFNB97, HGFR, RCCP2, c-Met

NCBI Gene: 4233 ENSG00000105976 UniProt: P08581

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]

Primary Disease Associations & Inheritance

?Arthrogryposis, distal, type 11MIM #620019

?Deafness, autosomal recessive 97MIM #616705

{Osteofibrous dysplasia, susceptibility to}MIM #607278

Hepatocellular carcinoma, childhood type, somaticMIM #114550

Renal cell carcinoma, papillary, 1, familial and somaticMIM #605074

376

ClinVar variants

Pathogenic / LP

0.97

pLI score· haploinsufficient

Active trials

Clinical Summary— MET

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Gene-Disease Validity (ClinGen)

papillary renal cell carcinoma · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

292 VUS of 376 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.30LOEUF

pLI 0.970

Z-score 6.01

OE 0.19 (0.12–0.30)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

1.92Z-score

OE missense 0.80 (0.75–0.86)

600 obs / 747.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.19 (0.12–0.30)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.80 (0.75–0.86)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.01

0≤1.21.6

LoF obs/exp: 12 / 63.8Missense obs/exp: 600 / 747.5Syn Z: -0.17

ClinVar Variant Classifications

376 submitted variants in ClinVar

ClinVar

Classification Summary

VUS292

Likely Benign84

292

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	26	242	20	4	292
Likely Benign	0	15	20	49	84
Benign	0	0	0	0	0
Total	26	257	40	53	376

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

MET · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

MET-related renal cell carcinoma, papillary

definitive

ADGain Of FunctionUncertain

Cancer

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

MET PROTOONCOGENE, RECEPTOR TYROSINE KINASE; MET

MIM #164860 · *

?Arthrogryposis, distal, type 11

MIM #620019