rs372238373

Variant summary

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

The NM_000245.4(MET):​c.3477C>G​(p.Tyr1159*) variant causes a stop gained change involving the alteration of a non-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 (★★). Synonymous variant affecting the same amino acid position (i.e. Y1159Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

MET
NM_000245.4 stop_gained

Scores

2
3
2

Clinical Significance

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

Conservation

PhyloP100: -0.0510
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.3477C>G p.Tyr1159* stop_gained 17/21 ENST00000397752.8 NP_000236.2 P08581-1A0A024R759
METNM_001127500.3 linkuse as main transcriptc.3531C>G p.Tyr1177* stop_gained 17/21 NP_001120972.1 P08581-2A0A024R728
METNM_001324402.2 linkuse as main transcriptc.2187C>G p.Tyr729* stop_gained 16/20 NP_001311331.1 B4DLF5
METXM_011516223.2 linkuse as main transcriptc.3534C>G p.Tyr1178* stop_gained 18/22 XP_011514525.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
METENST00000397752.8 linkuse as main transcriptc.3477C>G p.Tyr1159* stop_gained 17/211 NM_000245.4 ENSP00000380860.3 P08581-1
METENST00000318493.11 linkuse as main transcriptc.3531C>G p.Tyr1177* stop_gained 17/211 ENSP00000317272.6 P08581-2
METENST00000436117.3 linkuse as main transcriptn.*1082C>G non_coding_transcript_exon_variant 16/201 ENSP00000410980.2 P08581-3
METENST00000436117.3 linkuse as main transcriptn.*1082C>G 3_prime_UTR_variant 16/201 ENSP00000410980.2 P08581-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
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
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 26, 2024Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 11, 2022The p.Y1177* variant (also known as c.3531C>G), located in coding exon 16 of the MET gene, results from a C to G substitution at nucleotide position 3531. This changes the amino acid from a tyrosine to a stop codon within coding exon 16. This alteration is expected to result in premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of MET has not been clearly established as a mechanism of disease. 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
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
37
DANN
Uncertain
1.0
Eigen
Uncertain
0.38
Eigen_PC
Benign
0.17
FATHMM_MKL
Uncertain
0.86
D
Vest4
0.93
GERP RS
-0.10
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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: chr7-116418966; API