rs786204102
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The ENST00000397752.8(MET):c.3263A>G(p.His1088Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Consequence
MET
ENST00000397752.8 missense
ENST00000397752.8 missense
Scores
7
8
4
Clinical Significance
Conservation
PhyloP100: 9.32
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 5 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in ENST00000397752.8
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.832
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MET | NM_000245.4 | c.3263A>G | p.His1088Arg | missense_variant | 16/21 | ENST00000397752.8 | NP_000236.2 | |
MET | NM_001127500.3 | c.3317A>G | p.His1106Arg | missense_variant | 16/21 | NP_001120972.1 | ||
MET | NM_001324402.2 | c.1973A>G | p.His658Arg | missense_variant | 15/20 | NP_001311331.1 | ||
MET | XM_011516223.2 | c.3320A>G | p.His1107Arg | missense_variant | 17/22 | XP_011514525.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MET | ENST00000397752.8 | c.3263A>G | p.His1088Arg | missense_variant | 16/21 | 1 | NM_000245.4 | ENSP00000380860 | P3 | |
MET | ENST00000318493.11 | c.3317A>G | p.His1106Arg | missense_variant | 16/21 | 1 | ENSP00000317272 | A2 | ||
MET | ENST00000436117.3 | c.*868A>G | 3_prime_UTR_variant, NMD_transcript_variant | 15/20 | 1 | ENSP00000410980 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Renal cell carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 20, 2019 | In summary, this is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "deleterious"; PolyPhen-2: “possibly damaging”; Align-GVGD: "Class C0"). This sequence change has not been published in the literature and is not present in population databases. ClinVar contains an entry for this variant (Variation ID: 188147). This sequence change replaces histidine with arginine at codon 1106 of the MET protein (p.His1106Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Benign
N;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Gain of methylation at H1088 (P = 0.0143);.;
MVP
MPC
0.98
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at