NM_000245.4:c.788C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_000245.4(MET):​c.788C>T​(p.Thr263Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000254 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T263A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

MET
NM_000245.4 missense

Scores

7
9
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 5.83
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.788

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
METNM_000245.4 linkc.788C>T p.Thr263Met missense_variant Exon 2 of 21 ENST00000397752.8 NP_000236.2 P08581-1A0A024R759

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
METENST00000397752.8 linkc.788C>T p.Thr263Met missense_variant Exon 2 of 21 1 NM_000245.4 ENSP00000380860.3 P08581-1
METENST00000318493.11 linkc.788C>T p.Thr263Met missense_variant Exon 2 of 21 1 ENSP00000317272.6 P08581-2
METENST00000436117.3 linkn.788C>T non_coding_transcript_exon_variant Exon 2 of 20 1 ENSP00000410980.2 P08581-3
METENST00000422097.2 linkc.788C>T p.Thr263Met missense_variant Exon 2 of 12 3 ENSP00000398776.2 H7C174

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152146
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
249120
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135136
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000464
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000253
AC:
37
AN:
1461794
Hom.:
0
Cov.:
32
AF XY:
0.0000261
AC XY:
19
AN XY:
727198
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000288
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152146
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000166
AC:
2
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 97 Uncertain:1
Sep 20, 2023
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Renal cell carcinoma Uncertain:1
Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 263 of the MET protein (p.Thr263Met). This variant is present in population databases (rs764052874, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with MET-related conditions. ClinVar contains an entry for this variant (Variation ID: 485747). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MET protein function. In 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. -

not provided Uncertain:1
Jan 27, 2022
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Papillary renal cell carcinoma type 1 Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hereditary cancer-predisposing syndrome Uncertain:1
Jun 07, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.T263M variant (also known as c.788C>T), located in coding exon 1 of the MET gene, results from a C to T substitution at nucleotide position 788. The threonine at codon 263 is replaced by methionine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.050
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.53
D;.;.
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Benign
0.074
D
MetaRNN
Pathogenic
0.79
D;D;D
MetaSVM
Benign
-0.78
T
MutationAssessor
Uncertain
2.7
M;M;M
PrimateAI
Uncertain
0.54
T
PROVEAN
Pathogenic
-4.6
D;D;D
REVEL
Uncertain
0.37
Sift
Uncertain
0.0010
D;D;D
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
1.0
D;D;.
Vest4
0.82
MVP
0.62
MPC
0.91
ClinPred
0.98
D
GERP RS
6.1
Varity_R
0.71
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs764052874; hg19: chr7-116339926; COSMIC: COSV59258977; COSMIC: COSV59258977; API