rs180985111

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000245.4(MET):c.71G>A(p.Gly24Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000979 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

MET
NM_000245.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:6O:1

Conservation

PhyloP100: 3.04

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02822575).

BP6

Variant 7-116699155-G-A is Benign according to our data. Variant chr7-116699155-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134649.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4, not_provided=1, Benign=1}. Variant chr7-116699155-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000506 (77/152208) while in subpopulation AFR AF= 0.00181 (75/41530). AF 95% confidence interval is 0.00148. There are 0 homozygotes in gnomad4. There are 38 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	Protein	UniProt
MET	NM_000245.4 linkuse as main transcript	c.71G>A	p.Gly24Glu	missense_variant	2/21	ENST00000397752.8	NP_000236.2	P08581-1A0A024R759

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8 linkuse as main transcript	c.71G>A	p.Gly24Glu	missense_variant	2/21	1	NM_000245.4	ENSP00000380860.3		P08581-1

Frequencies

GnomAD3 genomes

AF:

0.000500

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000140

AC:

AN:

249366

Hom.:

AF XY:

0.000126

AC XY:

AN XY:

135284

show subpopulations

Gnomad AFR exome

AF:

0.00174

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000554

AC:

AN:

1461686

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.00143

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000506

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.00181

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000124

Hom.:

Bravo

AF:

0.000616

ESP6500AA

AF:

0.00102

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000174

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Vantari Genetics	Dec 07, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 11, 2020	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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 01, 2021	- -

not specified

Uncertain:1Benign:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 29, 2024	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 07, 2024

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with lymphedema or breast cancer (PMID: 18564920, 35264596); This variant is associated with the following publications: (PMID: 24728327, 25637381, 32171644, 24339735, 30530636, 35264596, 18564920) -

MET-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Renal cell carcinoma

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Lymphedema

Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Papillary renal cell carcinoma type 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jul 02, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.66

.;D;.;.

Eigen

Benign

0.046

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.87

D;D;D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.028

T;T;T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.4

.;L;L;L

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.6

D;D;D;D

REVEL

Benign

0.17

Sift

Benign

0.062

T;D;D;T

Sift4G

Uncertain

0.014

D;T;T;T

Polyphen

0.017, 0.088

.;B;B;.

Vest4

0.33, 0.39, 0.31

MVP

0.89

MPC

0.84

ClinPred

0.025

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.28

gMVP

0.69

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