rs121913246

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_000245.4(MET):c.3689A>G(p.Tyr1230Cys) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1230D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MET
NM_000245.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 5.01

Publications

70 publications found

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]

MET Gene-Disease associations (from GenCC):

hereditary papillary renal cell carcinoma
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
papillary renal cell carcinoma
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen
autosomal recessive nonsyndromic hearing loss 97
Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
osteofibrous dysplasia
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
arthrogryposis, distal, IIa 11
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
nonsyndromic genetic hearing loss
Inheritance: AR Classification: LIMITED Submitted by: ClinGen
complex neurodevelopmental disorder
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MET links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_000245.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.873

PP5

Variant 7-116783360-A-G is Pathogenic according to our data. Variant chr7-116783360-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13885.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MET	NM_000245.4 link	c.3689A>G	p.Tyr1230Cys	missense_variant	Exon 19 of 21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3 link	c.3743A>G	p.Tyr1248Cys	missense_variant	Exon 19 of 21		NP_001120972.1
MET	NM_001324402.2 link	c.2399A>G	p.Tyr800Cys	missense_variant	Exon 18 of 20		NP_001311331.1
MET	XM_011516223.2 link	c.3746A>G	p.Tyr1249Cys	missense_variant	Exon 20 of 22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MET	ENST00000397752.8 link	c.3689A>G	p.Tyr1230Cys	missense_variant	Exon 19 of 21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11 link	c.3743A>G	p.Tyr1248Cys	missense_variant	Exon 19 of 21	1		ENSP00000317272.6
MET	ENST00000436117.3 link	n.*1294A>G		non_coding_transcript_exon_variant	Exon 18 of 20	1		ENSP00000410980.2
MET	ENST00000436117.3 link	n.*1294A>G		3_prime_UTR_variant	Exon 18 of 20	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

249280

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727220

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111984

Other (OTH)

AF:

0.00

AC:

AN:

60392

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Papillary renal cell carcinoma type 1

Pathogenic:2

May 01, 1997

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 02, 2023

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9140397, 34882875]. Functional studies indicate this variant impacts protein function [PMID: 9326629, 9826708, 10498872]. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Jun 29, 2021

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Y1248C variant (also known as c.3743A>G), located in coding exon 18 of the MET gene, results from an A to G substitution at nucleotide position 3743. The tyrosine at codon 1248 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant is reported in an individual with bilateral papillary renal cell carcinoma and gastric cancer (Schmidt L et al. Nat Genet, 1997 May;16:68-73). Functional studies indicate that the p.Y1248C alteration increases tyrosine kinase activity and confers cell transformation properties (Jeffers M et al. Proc Natl Acad Sci U S A, 1997 Oct;94:11445-50). Based on structural analysis, this variant is located in the tyrosine kinase domain and is mildly destabilizing to the local structure (Yuan H et al. Eur J Med Chem, 2018 Jan;143:491-502; Ambry internal data). This amino acid position is well conserved in available vertebrate species.This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Renal cell carcinoma

Uncertain:1

Sep 23, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Experimental studies have shown that this variant affects MET protein function (PMID: 9826708). This variant has been observed in an individual with bilateral papillary renal carcinoma, stomach cancer, and rectal cancer (PMID: 9140397). ClinVar contains an entry for this variant (Variation ID: 13885). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with cysteine at codon 1248 of the MET protein (p.Tyr1248Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.70

T;T

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Uncertain

0.60

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

5.0

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

D;D

Vest4

0.83

MutPred

0.68

Loss of phosphorylation at Y1230 (P = 0.0464);.;

MVP

0.95

MPC

2.1

ClinPred

1.0

GERP RS

5.5

Varity_R

0.95

gMVP

0.93

Mutation Taster

=13/87

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over