rs41737

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000245.4(MET):c.4092G>A(p.Pro1364Pro) 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:16

Conservation

PhyloP100: -1.06

Publications

39 publications found

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 Gene-Disease associations (from GenCC):

hereditary papillary renal cell carcinoma
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
papillary renal cell carcinoma
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen
autosomal recessive nonsyndromic hearing loss 97
Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
osteofibrous dysplasia
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
arthrogryposis, distal, IIa 11
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
nonsyndromic genetic hearing loss
Inheritance: AR Classification: LIMITED Submitted by: ClinGen
complex neurodevelopmental disorder
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MET links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 93576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein
MET	NM_000245.4 link	c.4092G>A	p.Pro1364Pro	synonymous_variant	Exon 21 of 21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3 link	c.4146G>A	p.Pro1382Pro	synonymous_variant	Exon 21 of 21		NP_001120972.1
MET	NM_001324402.2 link	c.2802G>A	p.Pro934Pro	synonymous_variant	Exon 20 of 20		NP_001311331.1
MET	XM_011516223.2 link	c.4149G>A	p.Pro1383Pro	synonymous_variant	Exon 22 of 22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MET	ENST00000397752.8 link	c.4092G>A	p.Pro1364Pro	synonymous_variant	Exon 21 of 21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11 link	c.4146G>A	p.Pro1382Pro	synonymous_variant	Exon 21 of 21	1		ENSP00000317272.6
MET	ENST00000436117.3 link	n.*1697G>A		non_coding_transcript_exon_variant	Exon 20 of 20	1		ENSP00000410980.2
MET	ENST00000436117.3 link	n.*1697G>A		3_prime_UTR_variant	Exon 20 of 20	1		ENSP00000410980.2

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

GnomAD2 exomes

AF:

0.435

AC:

108397

AN:

249274

AF XY:

0.437

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 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

African (AFR)

AF:

0.0895

AC:

2997

AN:

33480

American (AMR)

AF:

0.511

AC:

22845

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.490

AC:

12816

AN:

26132

East Asian (EAS)

AF:

0.490

AC:

19436

AN:

39698

South Asian (SAS)

AF:

0.455

AC:

39242

AN:

86254

European-Finnish (FIN)

AF:

0.399

AC:

21335

AN:

53416

Middle Eastern (MID)

AF:

0.428

AC:

2468

AN:

5768

European-Non Finnish (NFE)

AF:

0.451

AC:

501912

AN:

1111920

Other (OTH)

AF:

0.441

AC:

26657

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

24110

48219

72329

96438

120548

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15040

30080

45120

60160

75200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.351

AC:

53295

AN:

152010

Hom.:

11157

Cov.:

AF XY:

0.353

AC XY:

26216

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.103

AC:

4263

AN:

41484

American (AMR)

AF:

0.445

AC:

6800

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.487

AC:

1691

AN:

3472

East Asian (EAS)

AF:

0.471

AC:

2435

AN:

5166

South Asian (SAS)

AF:

0.456

AC:

2190

AN:

4806

European-Finnish (FIN)

AF:

0.382

AC:

4026

AN:

10530

Middle Eastern (MID)

AF:

0.412

AC:

121

AN:

294

European-Non Finnish (NFE)

AF:

0.451

AC:

30676

AN:

67964

Other (OTH)

AF:

0.387

AC:

815

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1598

3195

4793

6390

7988

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

520

1040

1560

2080

2600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.415

Hom.:

43395

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:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 30, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 19, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Papillary renal cell carcinoma type 1

Benign:3

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Nov 15, 2024

Myriad Genetics, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

not provided

Benign:2

Aug 18, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary cancer-predisposing syndrome

Benign:2

Nov 19, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 08, 2025

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BA1+BP6+BP7 -

Autosomal recessive nonsyndromic hearing loss 97

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Renal cell carcinoma

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

0.40

(source)

DANN

Benign

0.61

PhyloP100

-1.1

Mutation Taster

=79/21

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over