rs1554395889

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000245.4(MET):​c.2293A>G​(p.Lys765Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

MET
NM_000245.4 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 5.97
Variant links:
Genes affected
MET (HGNC:7029): (MET proto-oncogene, receptor tyrosine kinase) 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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
METNM_000245.4 linkuse as main transcriptc.2293A>G p.Lys765Glu missense_variant 10/21 ENST00000397752.8 NP_000236.2 P08581-1A0A024R759

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
METENST00000397752.8 linkuse as main transcriptc.2293A>G p.Lys765Glu missense_variant 10/211 NM_000245.4 ENSP00000380860.3 P08581-1
METENST00000318493.11 linkuse as main transcriptc.2347A>G p.Lys783Glu missense_variant 10/211 ENSP00000317272.6 P08581-2
METENST00000436117.3 linkuse as main transcriptn.2264+799A>G intron_variant 1 ENSP00000410980.2 P08581-3
METENST00000422097.2 linkuse as main transcriptc.2293A>G p.Lys765Glu missense_variant 10/123 ENSP00000398776.2 H7C174

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 31, 2024The p.K783E variant (also known as c.2347A>G), located in coding exon 9 of the MET gene, results from an A to G substitution at nucleotide position 2347. The lysine at codon 783 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submittercurationSema4, Sema4May 17, 2021- -
Renal cell carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 16, 2017In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MET-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with glutamic acid at codon 783 of the MET protein (p.Lys783Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 27, 2023Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.080
BayesDel_addAF
Uncertain
0.060
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.37
T;.;.
Eigen
Benign
0.050
Eigen_PC
Uncertain
0.22
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Benign
0.038
D
MetaRNN
Uncertain
0.46
T;T;T
MetaSVM
Benign
-0.70
T
MutationAssessor
Benign
1.2
L;.;.
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
0.030
N;N;N
REVEL
Benign
0.27
Sift
Benign
0.45
T;T;T
Sift4G
Benign
0.97
T;T;T
Polyphen
0.40
B;B;.
Vest4
0.32
MutPred
0.57
Loss of ubiquitination at K765 (P = 0.0116);.;.;
MVP
0.81
MPC
0.46
ClinPred
0.70
D
GERP RS
5.9
Varity_R
0.19
gMVP
0.78

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554395889; hg19: chr7-116399473; API