rs11762213

Positions:

Variant summary

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

The NM_000245.4(MET):c.144G>A(p.Ala48Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0456 in 1,613,846 control chromosomes in the GnomAD database, including 1,985 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 108 hom., cov: 32)

Exomes 𝑓: 0.047 ( 1877 hom. )

Consequence

MET
NM_000245.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.559

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=-0.74).

BP6

Variant 7-116699228-G-A is Benign according to our data. Variant chr7-116699228-G-A is described in ClinVar as [Benign]. Clinvar id is 93567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-116699228-G-A is described in Lovd as [Benign]. Variant chr7-116699228-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.559 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4 link	c.144G>A	p.Ala48Ala	synonymous_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 link	c.144G>A	p.Ala48Ala	synonymous_variant	2/21	1	NM_000245.4	ENSP00000380860.3		P08581-1

Frequencies

GnomAD3 genomes

AF:

0.0331

AC:

5028

AN:

152004

Hom.:

108

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0114

Gnomad AMI

AF:

0.0526

Gnomad AMR

AF:

0.0372

Gnomad ASJ

AF:

0.0351

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00686

Gnomad FIN

AF:

0.0153

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0519

Gnomad OTH

AF:

0.0415

GnomAD3 exomes

AF:

0.0332

AC:

8281

AN:

249368

Hom.:

211

AF XY:

0.0338

AC XY:

4570

AN XY:

135280

show subpopulations

Gnomad AFR exome

AF:

0.0110

Gnomad AMR exome

AF:

0.0253

Gnomad ASJ exome

AF:

0.0305

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0106

Gnomad FIN exome

AF:

0.0152

Gnomad NFE exome

AF:

0.0534

Gnomad OTH exome

AF:

0.0389

GnomAD4 exome

AF:

0.0469

AC:

68626

AN:

1461724

Hom.:

1877

Cov.:

AF XY:

0.0456

AC XY:

33156

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.00902

Gnomad4 AMR exome

AF:

0.0265

Gnomad4 ASJ exome

AF:

0.0289

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0108

Gnomad4 FIN exome

AF:

0.0152

Gnomad4 NFE exome

AF:

0.0559

Gnomad4 OTH exome

AF:

0.0395

GnomAD4 genome

AF:

0.0331

AC:

5028

AN:

152122

Hom.:

108

Cov.:

AF XY:

0.0310

AC XY:

2303

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0113

Gnomad4 AMR

AF:

0.0371

Gnomad4 ASJ

AF:

0.0351

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00707

Gnomad4 FIN

AF:

0.0153

Gnomad4 NFE

AF:

0.0519

Gnomad4 OTH

AF:

0.0411

Alfa

AF:

0.0488

Hom.:

268

Bravo

AF:

0.0350

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0520

EpiControl

AF:

0.0545

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 06, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2017	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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:4

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.144G>A (p.Ala48Ala) variant causes a synonymous change involving a non-conserved nucleotide. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 3980/120670 (1/30, 106 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 cite the variant as "benign." Therefore, the variant has been classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 30, 2018	- -

Papillary renal cell carcinoma type 1

Benign:2

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

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

Nov 19, 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

-0.74

CADD

Benign

0.40

DANN

Benign

0.54

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

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