rs13223756

Positions:

chr7-116757518-A-G

Variant summary

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

The ENST00000397752.8(MET):c.1944A>G(p.Gln648=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,612,994 control chromosomes in the GnomAD database, including 29,894 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2341 hom., cov: 32)

Exomes 𝑓: 0.19 ( 27553 hom. )

Consequence

MET
ENST00000397752.8 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.17

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=-0.85).

BP6

Variant 7-116757518-A-G is Benign according to our data. Variant chr7-116757518-A-G is described in ClinVar as [Benign]. Clinvar id is 93569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-116757518-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.17 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4 linkuse as main transcript	c.1944A>G	p.Gln648=	synonymous_variant	7/21	ENST00000397752.8	NP_000236.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8 linkuse as main transcript	c.1944A>G	p.Gln648=	synonymous_variant	7/21	1	NM_000245.4	ENSP00000380860	P3	P08581-1
MET	ENST00000318493.11 linkuse as main transcript	c.1944A>G	p.Gln648=	synonymous_variant	7/21	1		ENSP00000317272	A2	P08581-2
MET	ENST00000436117.3 linkuse as main transcript	c.1944A>G	p.Gln648=	synonymous_variant, NMD_transcript_variant	7/20	1		ENSP00000410980		P08581-3
MET	ENST00000422097.2 linkuse as main transcript	c.1944A>G	p.Gln648=	synonymous_variant	7/12	3		ENSP00000398776

Frequencies

GnomAD3 genomes

AF:

0.171

AC:

26008

AN:

152034

Hom.:

2342

Cov.:

show subpopulations

Gnomad AFR

AF:

0.129

Gnomad AMI

AF:

0.332

Gnomad AMR

AF:

0.125

Gnomad ASJ

AF:

0.213

Gnomad EAS

AF:

0.283

Gnomad SAS

AF:

0.230

Gnomad FIN

AF:

0.194

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.187

Gnomad OTH

AF:

0.158

GnomAD3 exomes

AF:

0.182

AC:

45494

AN:

249296

Hom.:

4535

AF XY:

0.188

AC XY:

25453

AN XY:

135246

show subpopulations

Gnomad AFR exome

AF:

0.125

Gnomad AMR exome

AF:

0.0804

Gnomad ASJ exome

AF:

0.196

Gnomad EAS exome

AF:

0.294

Gnomad SAS exome

AF:

0.231

Gnomad FIN exome

AF:

0.187

Gnomad NFE exome

AF:

0.189

Gnomad OTH exome

AF:

0.177

GnomAD4 exome

AF:

0.191

AC:

278297

AN:

1460842

Hom.:

27553

Cov.:

AF XY:

0.193

AC XY:

139975

AN XY:

726788

show subpopulations

Gnomad4 AFR exome

AF:

0.126

Gnomad4 AMR exome

AF:

0.0848

Gnomad4 ASJ exome

AF:

0.196

Gnomad4 EAS exome

AF:

0.272

Gnomad4 SAS exome

AF:

0.227

Gnomad4 FIN exome

AF:

0.191

Gnomad4 NFE exome

AF:

0.191

Gnomad4 OTH exome

AF:

0.187

GnomAD4 genome

AF:

0.171

AC:

26013

AN:

152152

Hom.:

2341

Cov.:

AF XY:

0.171

AC XY:

12756

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.129

Gnomad4 AMR

AF:

0.125

Gnomad4 ASJ

AF:

0.213

Gnomad4 EAS

AF:

0.284

Gnomad4 SAS

AF:

0.230

Gnomad4 FIN

AF:

0.194

Gnomad4 NFE

AF:

0.187

Gnomad4 OTH

AF:

0.159

Alfa

AF:

0.181

Hom.:

4341

Bravo

AF:

0.162

Asia WGS

AF:

0.251

AC:

873

AN:

3478

EpiCase

AF:

0.180

EpiControl

AF:

0.186

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 12, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2016	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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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.1944A>G (p.Gln648Gln) 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 22638/120534 (1/5, 2318 homozygotes), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic MET variant of 1/666666, suggesting this variant is likely a benign polymorphism. Multiple reputable clinical laboratories have cited the variant as "benign." Therefore, the variant of interest has been classified as Benign. -

Renal cell carcinoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 24, 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

-0.85

CADD

Benign

0.29

DANN

Benign

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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