7-116796101-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000245.4(MET):​c.4150G>C​(p.Ala1384Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

MET
NM_000245.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.209
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 2 ACMG points.

PM1
In a region_of_interest Interaction with RANBP9 (size 178) in uniprot entity MET_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000245.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.07916248).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
METNM_000245.4 linkc.4150G>C p.Ala1384Pro missense_variant Exon 21 of 21 ENST00000397752.8 NP_000236.2 P08581-1A0A024R759
METNM_001127500.3 linkc.4204G>C p.Ala1402Pro missense_variant Exon 21 of 21 NP_001120972.1 P08581-2A0A024R728
METNM_001324402.2 linkc.2860G>C p.Ala954Pro missense_variant Exon 20 of 20 NP_001311331.1 B4DLF5
METXM_011516223.2 linkc.4207G>C p.Ala1403Pro missense_variant Exon 22 of 22 XP_011514525.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
METENST00000397752.8 linkc.4150G>C p.Ala1384Pro missense_variant Exon 21 of 21 1 NM_000245.4 ENSP00000380860.3 P08581-1
METENST00000318493.11 linkc.4204G>C p.Ala1402Pro missense_variant Exon 21 of 21 1 ENSP00000317272.6 P08581-2
METENST00000436117.3 linkn.*1755G>C non_coding_transcript_exon_variant Exon 20 of 20 1 ENSP00000410980.2 P08581-3
METENST00000436117.3 linkn.*1755G>C 3_prime_UTR_variant Exon 20 of 20 1 ENSP00000410980.2 P08581-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jan 12, 2021
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed in large population cohorts (Lek 2016); 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 -

Hereditary cancer-predisposing syndrome Uncertain:1
Sep 30, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.A1402P variant (also known as c.4204G>C), located in coding exon 20 of the MET gene, results from a G to C substitution at nucleotide position 4204. The alanine at codon 1402 is replaced by proline, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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
Benign
0.074
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
5.4
DANN
Benign
0.49
DEOGEN2
Benign
0.30
T;.
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.23
N
LIST_S2
Benign
0.45
T;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.079
T;T
MetaSVM
Benign
-0.86
T
MutationAssessor
Benign
0.0
N;.
PrimateAI
Benign
0.25
T
PROVEAN
Benign
0.040
N;N
REVEL
Benign
0.16
Sift
Uncertain
0.027
D;D
Sift4G
Benign
0.27
T;T
Polyphen
0.0
B;B
Vest4
0.11
MutPred
0.20
Gain of catalytic residue at P1383 (P = 0.0164);.;
MVP
0.25
MPC
1.0
ClinPred
0.15
T
GERP RS
3.3
Varity_R
0.21
gMVP
0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-116436155; API