7-116771869-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000245.4(MET):c.2908C>T(p.Arg970Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00458 in 1,613,774 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 17 hom. )

Consequence

MET
NM_000245.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2B:20O:1

Conservation

PhyloP100: 3.57

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009256214).

BP6

Variant 7-116771869-C-T is Benign according to our data. Variant chr7-116771869-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 41623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-116771869-C-T is described in Lovd as [Likely_benign]. Variant chr7-116771869-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00312 (475/152220) while in subpopulation NFE AF= 0.00532 (362/68012). AF 95% confidence interval is 0.00487. There are 3 homozygotes in gnomad4. There are 209 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4 link	c.2908C>T	p.Arg970Cys	missense_variant	Exon 14 of 21	ENST00000397752.8	NP_000236.2	P08581-1A0A024R759
MET	NM_001127500.3 link	c.2962C>T	p.Arg988Cys	missense_variant	Exon 14 of 21		NP_001120972.1	P08581-2A0A024R728
MET	NM_001324402.2 link	c.1618C>T	p.Arg540Cys	missense_variant	Exon 13 of 20		NP_001311331.1	B4DLF5
MET	XM_011516223.2 link	c.2965C>T	p.Arg989Cys	missense_variant	Exon 15 of 22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8 link	c.2908C>T	p.Arg970Cys	missense_variant	Exon 14 of 21	1	NM_000245.4	ENSP00000380860.3		P08581-1

Frequencies

GnomAD3 genomes

AF:

0.00312

AC:

475

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.00158

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00532

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00288

AC:

717

AN:

248552

Hom.:

AF XY:

0.00297

AC XY:

400

AN XY:

134820

show subpopulations

Gnomad AFR exome

AF:

0.000904

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.000223

Gnomad SAS exome

AF:

0.000654

Gnomad FIN exome

AF:

0.000929

Gnomad NFE exome

AF:

0.00520

Gnomad OTH exome

AF:

0.00332

GnomAD4 exome

AF:

0.00473

AC:

6915

AN:

1461554

Hom.:

Cov.:

AF XY:

0.00453

AC XY:

3291

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.000986

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.00145

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000730

Gnomad4 FIN exome

AF:

0.00124

Gnomad4 NFE exome

AF:

0.00583

Gnomad4 OTH exome

AF:

0.00283

GnomAD4 genome

AF:

0.00312

AC:

475

AN:

152220

Hom.:

Cov.:

AF XY:

0.00281

AC XY:

209

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000867

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000943

Gnomad4 NFE

AF:

0.00532

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00492

Hom.:

Bravo

AF:

0.00328

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.000798

AC:

ESP6500EA

AF:

0.00475

AC:

ExAC

AF:

0.00284

AC:

343

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00720

EpiControl

AF:

0.00569

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2Benign:20Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:9

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Oct 06, 2023	BA1 based on allele frequency in NFE of 0.0050422 in gnomAD. PMID:20670955 variant lacks transforming ability. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 24, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	MET: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2019	This variant is associated with the following publications: (PMID: 17322284, 17053076, 20670955, 25314153, 20368753, 23401458, 22128285, 25231402, 16734685, 25992381, 27626278, 28085233, 27636102, no PMID, 29970518, 14559814, 24728327, 23449277, 16189274, 15592501, 21847116, 15735036, 19723643, 26097886, 18564920, 22703879, 17404109, 23640142, 20370683, 20139696, 19037978, 18340114, 19318576, 17288874, 19861919, 17483355, 23662036, 19333071, 18709663, 20462834, 22838389, 20489150, 19393836, 21918175, 22530990, 25868855, 24327519, 24105670, 25416047, 24929890, 22973954, 26574927, 27153395, 28648934, 28116210, 27741505, 27899992, 28247034, 27013592, 28061464, 26934580, 27376238, 28603720, 28740441, 27923392, 28476232, 28619094, 31004003) -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Feb 18, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified

Uncertain:1Benign:3Other:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Mar 04, 2025	- -
Uncertain significance, flagged submission	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gene associated with cancers, and variant has been identified in large B-cell lymphoma, but also pretty high frequency in ExAC with 1 homozygote, reported in apparently healthy individuals, and there are conflicting reports about functional impact (most recent functional study says no impact) -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 04, 2021	- -

Papillary renal cell carcinoma type 1

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jan 21, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 23, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 27, 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. -

MET-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 07, 2019

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 04, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;.

Eigen

Benign

-0.11

Eigen_PC

Benign

0.092

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.0093

T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.0

N;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.79

N;N

REVEL

Benign

0.17

Sift

Uncertain

0.027

D;D

Sift4G

Benign

0.18

T;T

Polyphen

0.026

B;B

Vest4

0.37

MVP

0.66

MPC

0.35

ClinPred

0.19

GERP RS

4.9

Varity_R

0.27

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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