rs201687037

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_000245.4(MET):c.901A>G(p.Thr301Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000568 in 1,614,046 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T301T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 1 hom. )

Consequence

MET
NM_000245.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:3O:1

Conservation

PhyloP100: 5.63

Publications

6 publications found

Variant links:

COSMIC-nc: COSV59258101

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:

COMETT (HGNC:51196): (cytosolic oncogenic antisense to MET transcript) This gene encodes a natural antisense transcript highly expressed in papillary thyroid carcinomas harboring BRAF V600E mutation or RET gene rearrangements. This lncRNA induces the downstream MAPK pathway and is part of a co-expression network including different oncogenes belonging to the MAPK and PI3H/AKT pathways. In thyroid carcinomas, this gene has oncogenic properties associated with increased proliferation and drug resistance. [provided by RefSeq, Jan 2020]

COMETT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10883194).

BP6

Variant 7-116699985-A-G is Benign according to our data. Variant chr7-116699985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167292. Variant chr7-116699985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167292. Variant chr7-116699985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167292. Variant chr7-116699985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167292. Variant chr7-116699985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167292. Variant chr7-116699985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167292. Variant chr7-116699985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167292. Variant chr7-116699985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167292. Variant chr7-116699985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167292. Variant chr7-116699985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167292.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000355 (54/152296) while in subpopulation NFE AF = 0.000647 (44/68024). AF 95% confidence interval is 0.000495. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4 link	c.901A>G	p.Thr301Ala	missense_variant	Exon 2 of 21	ENST00000397752.8	NP_000236.2	P08581-1A0A024R759

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8 link	c.901A>G	p.Thr301Ala	missense_variant	Exon 2 of 21	1	NM_000245.4	ENSP00000380860.3		P08581-1

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000289

AC:

AN:

248896

AF XY:

0.000252

show subpopulations

Gnomad AFR exome

AF:

0.000388

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000559

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000590

AC:

862

AN:

1461750

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

420

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33466

American (AMR)

AF:

0.0000447

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000755

AC:

840

AN:

1111950

Other (OTH)

AF:

0.000281

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

102

154

205

256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.000355

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41562

American (AMR)

AF:

0.0000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000647

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000480

Hom.:

Bravo

AF:

0.000302

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00109

AC:

ESP6500EA

AF:

0.000489

AC:

ExAC

AF:

0.000215

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5Other:1

Nov 13, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 29, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27696107, 34882875, 37316882) -

Oct 23, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MET c.901A>G, p.Thr301Ala variant (rs201687037), to our knowledge, has not been reported in the medical literature; however, this variant is listed in the ClinVar database (Variation ID: 167292). This variant is found in the general population with an overall allele frequency of 0.03% (81/280,300 alleles) in the Genome Aggregation Database. The threonine at codon 301 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.243). Based on the available information, the clinical significance of this variant is uncertain. -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MET p.T301A variant was identified in one individual with colon cancer (Rohlin_2017_PMID: 27696107). The variant was identified in dbSNP (ID: rs201687037), ClinVar (classified as uncertain significance by EGL Genetic Diagnostics and Invitae; and as likely benign by Ambry Genetics), and COSMIC (lung, prostate, endometrium). The variant was identified in control databases in 81 of 280300 chromosomes at a frequency of 0.0002890, and was observed at the highest frequency in the European (non-Finnish) population in 71 of 128168 chromosomes (freq: 0.0005540) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.T301 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict an impact on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Jan 15, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant classified as Uncertain significance and reported on 03-08-2018 by GeneDx. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not specified

Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 97

Uncertain:1

May 14, 2018

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Hereditary papillary renal cell carcinoma

Uncertain:1

Feb 17, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Renal cell carcinoma

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Papillary renal cell carcinoma type 1

Benign:1

Nov 06, 2024

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Hereditary cancer-predisposing syndrome

Benign:1

Sep 10, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;.;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.5

L;L;L

PhyloP100

5.6

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.29

N;N;N

REVEL

Benign

0.24

Sift

Benign

0.054

T;D;T

Sift4G

Benign

0.40

T;T;D

Polyphen

1.0

D;D;.

Vest4

0.69

MVP

0.44

MPC

0.88

ClinPred

0.053

GERP RS

6.2

Varity_R

0.39

gMVP

0.37

Mutation Taster

=43/57

disease causing

(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