rs41737

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000245.4(MET):c.4092G>A(p.Pro1364=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 1,613,794 control chromosomes in the GnomAD database, including 158,361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 11157 hom., cov: 32)

Exomes 𝑓: 0.44 ( 147204 hom. )

Consequence

MET
NM_000245.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -1.06

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 7-116796043-G-A is Benign according to our data. Variant chr7-116796043-G-A is described in ClinVar as [Benign]. Clinvar id is 93576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-116796043-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.06 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MET	NM_000245.4 linkuse as main transcript	c.4092G>A	p.Pro1364=	synonymous_variant	21/21	ENST00000397752.8
MET	NM_001127500.3 linkuse as main transcript	c.4146G>A	p.Pro1382=	synonymous_variant	21/21
MET	NM_001324402.2 linkuse as main transcript	c.2802G>A	p.Pro934=	synonymous_variant	20/20
MET	XM_011516223.2 linkuse as main transcript	c.4149G>A	p.Pro1383=	synonymous_variant	22/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MET	ENST00000397752.8 linkuse as main transcript	c.4092G>A	p.Pro1364=	synonymous_variant	21/21	1	NM_000245.4	P3	P08581-1
MET	ENST00000318493.11 linkuse as main transcript	c.4146G>A	p.Pro1382=	synonymous_variant	21/21	1		A2	P08581-2
MET	ENST00000436117.3 linkuse as main transcript	c.*1697G>A		3_prime_UTR_variant, NMD_transcript_variant	20/20	1			P08581-3

Frequencies

GnomAD3 genomes

AF:

0.351

AC:

53319

AN:

151892

Hom.:

11170

Cov.:

show subpopulations

Gnomad AFR

AF:

0.103

Gnomad AMI

AF:

0.305

Gnomad AMR

AF:

0.445

Gnomad ASJ

AF:

0.487

Gnomad EAS

AF:

0.471

Gnomad SAS

AF:

0.457

Gnomad FIN

AF:

0.382

Gnomad MID

AF:

0.430

Gnomad NFE

AF:

0.451

Gnomad OTH

AF:

0.392

GnomAD3 exomes

AF:

0.435

AC:

108397

AN:

249274

Hom.:

24780

AF XY:

0.437

AC XY:

59126

AN XY:

135226

show subpopulations

Gnomad AFR exome

AF:

0.0920

Gnomad AMR exome

AF:

0.519

Gnomad ASJ exome

AF:

0.487

Gnomad EAS exome

AF:

0.459

Gnomad SAS exome

AF:

0.460

Gnomad FIN exome

AF:

0.394

Gnomad NFE exome

AF:

0.447

Gnomad OTH exome

AF:

0.457

GnomAD4 exome

AF:

0.444

AC:

649708

AN:

1461784

Hom.:

147204

Cov.:

AF XY:

0.446

AC XY:

324023

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.0895

Gnomad4 AMR exome

AF:

0.511

Gnomad4 ASJ exome

AF:

0.490

Gnomad4 EAS exome

AF:

0.490

Gnomad4 SAS exome

AF:

0.455

Gnomad4 FIN exome

AF:

0.399

Gnomad4 NFE exome

AF:

0.451

Gnomad4 OTH exome

AF:

0.441

GnomAD4 genome

AF:

0.351

AC:

53295

AN:

152010

Hom.:

11157

Cov.:

AF XY:

0.353

AC XY:

26216

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.103

Gnomad4 AMR

AF:

0.445

Gnomad4 ASJ

AF:

0.487

Gnomad4 EAS

AF:

0.471

Gnomad4 SAS

AF:

0.456

Gnomad4 FIN

AF:

0.382

Gnomad4 NFE

AF:

0.451

Gnomad4 OTH

AF:

0.387

Alfa

AF:

0.433

Hom.:

29496

Bravo

AF:

0.346

Asia WGS

AF:

0.415

AC:

1444

AN:

3478

EpiCase

AF:

0.452

EpiControl

AF:

0.450

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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 12, 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

- -

not provided

Benign:1

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.4146G>A (p.Pro1382Pro) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools predicting no significant effect on splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 51284/120730 (1/ no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of ***. However, these predictions have yet to be confirmed by functional studies. This variant was found in 51284/120730 control chromosomes (1/2, 11610 homozygotes), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic MET variant of 1/666666. In addition, multiple reputable clinical laboratories cite the variant as "benign." Therefore, the variant of interest has been classified as Benign. -

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

-0.33

Cadd

Benign

0.40

Dann

Benign

0.61

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