7-116699551-C-T

Position:

chr7-116699551-C-T

Variant summary

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

The NM_000245.4(MET):c.467C>T(p.Ser156Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,613,974 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). Synonymous variant affecting the same amino acid position (i.e. S156S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

MET
NM_000245.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 1.87

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=0.015134901).

BP6

Variant 7-116699551-C-T is Benign according to our data. Variant chr7-116699551-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135971.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2, Benign=1}. Variant chr7-116699551-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000598 (91/152266) while in subpopulation AFR AF= 0.00149 (62/41566). AF 95% confidence interval is 0.00119. There are 0 homozygotes in gnomad4. There are 44 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.467C>T	p.Ser156Leu	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.467C>T	p.Ser156Leu	missense_variant	2/21	1	NM_000245.4	ENSP00000380860.3		P08581-1

Frequencies

GnomAD3 genomes

AF:

0.000598

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.000218

AC:

AN:

248200

Hom.:

AF XY:

0.000201

AC XY:

AN XY:

134660

show subpopulations

Gnomad AFR exome

AF:

0.00181

Gnomad AMR exome

AF:

0.000377

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:

0.0000892

Gnomad OTH exome

AF:

0.000498

GnomAD4 exome

AF:

0.000190

AC:

278

AN:

1461708

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

146

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.00149

Gnomad4 AMR exome

AF:

0.000425

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:

0.000160

Gnomad4 OTH exome

AF:

0.000480

GnomAD4 genome

AF:

0.000598

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00149

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.000177

Hom.:

Bravo

AF:

0.000737

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00173

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000199

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 21, 2018	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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 18, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2024

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer in published literature (PMID: 35264596); This variant is associated with the following publications: (PMID: 29084058, 34513100, 29212164, 36431263, 35264596, 37835473) -

MET-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 21, 2020

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 24, 2024

- -

Papillary renal cell carcinoma type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

.;T;.;.

Eigen

Benign

-0.027

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.14

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.015

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

.;M;M;M

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.1

N;D;D;N

REVEL

Benign

0.14

Sift

Uncertain

0.0060

D;T;T;D

Sift4G

Uncertain

0.0080

D;D;D;D

Polyphen

0.89, 0.83

.;P;P;.

Vest4

0.47, 0.36, 0.44

MVP

0.42

MPC

0.31

ClinPred

0.025

GERP RS

3.9

Varity_R

0.12

gMVP

0.43

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