rs35775721

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000245.4(MET):c.534C>T(p.Ser178=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0482 in 1,613,868 control chromosomes in the GnomAD database, including 2,680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.072 ( 559 hom., cov: 32)

Exomes 𝑓: 0.046 ( 2121 hom. )

Consequence

MET
NM_000245.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.145

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 7-116699618-C-T is Benign according to our data. Variant chr7-116699618-C-T is described in ClinVar as [Benign]. Clinvar id is 93578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-116699618-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.145 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MET	NM_000245.4 linkuse as main transcript	c.534C>T	p.Ser178=	synonymous_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.534C>T	p.Ser178=	synonymous_variant	2/21	1	NM_000245.4	P3	P08581-1

Frequencies

GnomAD3 genomes

AF:

0.0718

AC:

10922

AN:

152076

Hom.:

556

Cov.:

show subpopulations

Gnomad AFR

AF:

0.138

Gnomad AMI

AF:

0.0548

Gnomad AMR

AF:

0.0432

Gnomad ASJ

AF:

0.0329

Gnomad EAS

AF:

0.0628

Gnomad SAS

AF:

0.110

Gnomad FIN

AF:

0.0533

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0411

Gnomad OTH

AF:

0.0761

GnomAD3 exomes

AF:

0.0566

AC:

13979

AN:

247062

Hom.:

618

AF XY:

0.0590

AC XY:

7914

AN XY:

134114

show subpopulations

Gnomad AFR exome

AF:

0.141

Gnomad AMR exome

AF:

0.0254

Gnomad ASJ exome

AF:

0.0324

Gnomad EAS exome

AF:

0.0666

Gnomad SAS exome

AF:

0.116

Gnomad FIN exome

AF:

0.0488

Gnomad NFE exome

AF:

0.0406

Gnomad OTH exome

AF:

0.0537

GnomAD4 exome

AF:

0.0458

AC:

66881

AN:

1461674

Hom.:

2121

Cov.:

AF XY:

0.0479

AC XY:

34819

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.143

Gnomad4 AMR exome

AF:

0.0273

Gnomad4 ASJ exome

AF:

0.0344

Gnomad4 EAS exome

AF:

0.0511

Gnomad4 SAS exome

AF:

0.113

Gnomad4 FIN exome

AF:

0.0498

Gnomad4 NFE exome

AF:

0.0375

Gnomad4 OTH exome

AF:

0.0544

GnomAD4 genome

AF:

0.0719

AC:

10944

AN:

152194

Hom.:

559

Cov.:

AF XY:

0.0715

AC XY:

5322

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.138

Gnomad4 AMR

AF:

0.0433

Gnomad4 ASJ

AF:

0.0329

Gnomad4 EAS

AF:

0.0625

Gnomad4 SAS

AF:

0.110

Gnomad4 FIN

AF:

0.0533

Gnomad4 NFE

AF:

0.0411

Gnomad4 OTH

AF:

0.0758

Alfa

AF:

0.0494

Hom.:

156

Bravo

AF:

0.0724

Asia WGS

AF:

0.0990

AC:

343

AN:

3478

EpiCase

AF:

0.0416

EpiControl

AF:

0.0429

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 09, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2016	Variant summary: The MET c.534C>T (p.Ser178Ser) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools predicting no significant impact on splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 7173/120102 (1/16, 337 homozygotes), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic MET variant o f 1/666666. Multiple reputable clinical laboratories have cited the variant as "benign." Therefore, the variant of interest has been classified as Benign. -

Papillary renal cell carcinoma type 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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. -

Autosomal recessive nonsyndromic hearing loss 97

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Renal cell carcinoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 28, 2014

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

BayesDel_noAF

Benign

-0.54

Cadd

Benign

6.4

Dann

Benign

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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