rs766929091

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PVS1_SupportingBS1_Supporting

The NM_001324402.2(MET):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

MET
NM_001324402.2 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 1.75

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 33 codons. Genomic position: 116731854. Lost 0.034 part of the original CDS.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00000821 (12/1461812) while in subpopulation SAS AF= 0.000128 (11/86256). AF 95% confidence interval is 0.0000712. There are 0 homozygotes in gnomad4_exome. There are 8 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4 link	c.1291A>G	p.Met431Val	missense_variant	Exon 3 of 21	ENST00000397752.8	NP_000236.2	P08581-1A0A024R759

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8 link	c.1291A>G	p.Met431Val	missense_variant	Exon 3 of 21	1	NM_000245.4	ENSP00000380860.3		P08581-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000321

AC:

AN:

249462

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135344

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:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461812

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727204

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:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000662

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

MET-related disorder

Uncertain:1

Aug 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MET c.1A>G variant is predicted to disrupt the translation initiation site (Start Loss). This variant is also known as c.1291A>G (p.Met431Val) under the hereditary cancer primary transcript NM_000245.4. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.026% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as a variant of uncertain significance by majority of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/572844/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Renal cell carcinoma

Uncertain:1

Jul 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt 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. ClinVar contains an entry for this variant (Variation ID: 572844). This variant has not been reported in the literature in individuals affected with MET-related conditions. This variant is present in population databases (rs766929091, gnomAD 0.03%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 431 of the MET protein (p.Met431Val). -

not provided

Uncertain:1

Nov 07, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Arthrogryposis, distal, IIa 11

Uncertain:1

Feb 14, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.1291A>G (p.Met431Val) variant in MET gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Met431Va variant has allele frequency 0.003% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance. The amino acid change p.Met431Val in MET is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Met at position 431 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -

Hereditary cancer-predisposing syndrome

Benign:1

Nov 21, 2023

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.44

DEOGEN2

Benign

0.26

T;.;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.0051

MetaRNN

Benign

0.22

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L;L

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.13

Sift

Benign

0.54

T;T;T

Sift4G

Benign

0.24

T;T;T

Polyphen

0.030

B;B;.

Vest4

0.55

MutPred

0.64

Loss of catalytic residue at V427 (P = 0.0331);Loss of catalytic residue at V427 (P = 0.0331);Loss of catalytic residue at V427 (P = 0.0331);

MVP

0.64

MPC

0.26

ClinPred

0.038

GERP RS

1.9

Varity_R

0.24

gMVP

0.55

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over