7-116700160-G-A

Position:

chr7-116700160-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_000245.4(MET):c.1076G>A(p.Arg359Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000317 in 1,594,300 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign 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. R359L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 1 hom. )

Consequence

MET
NM_000245.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 4.29

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12936655).

BP6

Variant 7-116700160-G-A is Benign according to our data. Variant chr7-116700160-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 93564.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000236 (36/152292) while in subpopulation NFE AF= 0.000397 (27/68016). AF 95% confidence interval is 0.00028. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MET	NM_000245.4 linkuse as main transcript	c.1076G>A	p.Arg359Gln	missense_variant	2/21	ENST00000397752.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MET	ENST00000397752.8 linkuse as main transcript	c.1076G>A	p.Arg359Gln	missense_variant	2/21	1	NM_000245.4	P3	P08581-1
MET	ENST00000318493.11 linkuse as main transcript	c.1076G>A	p.Arg359Gln	missense_variant	2/21	1		A2	P08581-2
MET	ENST00000436117.3 linkuse as main transcript	c.1076G>A	p.Arg359Gln	missense_variant, NMD_transcript_variant	2/20	1			P08581-3
MET	ENST00000422097.2 linkuse as main transcript	c.1076G>A	p.Arg359Gln	missense_variant	2/12	3

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000228

AC:

AN:

232152

Hom.:

AF XY:

0.000295

AC XY:

AN XY:

125308

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.000189

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000392

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000409

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000325

AC:

469

AN:

1442008

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

221

AN XY:

715342

show subpopulations

Gnomad4 AFR exome

AF:

0.0000920

Gnomad4 AMR exome

AF:

0.000167

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000122

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000408

Gnomad4 OTH exome

AF:

0.000134

GnomAD4 genome

AF:

0.000236

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000349

Hom.:

Bravo

AF:

0.000280

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000256

AC:

ESP6500EA

AF:

0.000361

AC:

ExAC

AF:

0.000248

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Published functional studies suggest this variant may increase MET expression but does not appear to impact cell migration or invasion (PMID: 34389035); Observed in individuals with thyroid cancer and breast cancer (PMID: 30086788, 34389035, 35264596); This variant is associated with the following publications: (PMID: 26718692, 28192086, 29049316, Rastegar2021[abstract], 34389035, 23334666, 26700204, 28873162, 28619094, 30086788, 35264596) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 01, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Renal cell carcinoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 359 of the MET protein (p.Arg359Gln). This variant is present in population databases (rs201274041, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with MET-related conditions. ClinVar contains an entry for this variant (Variation ID: 93564). 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 with a negative predictive value of 80%. 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. -

Papillary renal cell carcinoma type 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Sep 11, 2024

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2020

This alteration is classified as likely 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

0.084

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;.;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.0070

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.6

L;L;L

MutationTaster

Benign

0.97

D;D;D

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.51

N;N;N

REVEL

Benign

0.19

Sift

Benign

0.051

T;D;D

Sift4G

Benign

0.41

T;T;D

Polyphen

1.0

D;D;.

Vest4

0.27

MVP

0.46

MPC

0.85

ClinPred

0.070

GERP RS

6.0

Varity_R

0.29

gMVP

0.45

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