7-116700216-G-A

Variant names:

Variant summary

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

The NM_000245.4(MET):c.1132G>A(p.Val378Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000407 in 1,596,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V378G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

MET
NM_000245.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:5

Conservation

PhyloP100: 5.73

Publications

3 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 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=0.18482578).

BP6

Variant 7-116700216-G-A is Benign according to our data. Variant chr7-116700216-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 188364. Variant chr7-116700216-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 188364. Variant chr7-116700216-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 188364. Variant chr7-116700216-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 188364. Variant chr7-116700216-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 188364. Variant chr7-116700216-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 188364. Variant chr7-116700216-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 188364. Variant chr7-116700216-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 188364. Variant chr7-116700216-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 188364. Variant chr7-116700216-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 188364.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000394 (6/152142) while in subpopulation NFE AF = 0.0000735 (5/68008). AF 95% confidence interval is 0.0000285. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4 link	c.1132G>A	p.Val378Ile	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.1132G>A	p.Val378Ile	missense_variant	Exon 2 of 21	1	NM_000245.4	ENSP00000380860.3		P08581-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000433

AC:

AN:

230896

AF XY:

0.0000640

show subpopulations

Gnomad AFR exome

AF:

0.0000658

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000585

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000651

Gnomad OTH exome

AF:

0.000182

GnomAD4 exome

AF:

0.0000409

AC:

AN:

1443950

Hom.:

Cov.:

AF XY:

0.0000390

AC XY:

AN XY:

717536

show subpopulations

African (AFR)

AF:

0.0000309

AC:

AN:

32414

American (AMR)

AF:

0.0000248

AC:

AN:

40276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25048

East Asian (EAS)

AF:

0.000151

AC:

AN:

39630

South Asian (SAS)

AF:

0.0000610

AC:

AN:

81924

European-Finnish (FIN)

AF:

0.0000947

AC:

AN:

52786

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

0.0000343

AC:

AN:

1106648

Other (OTH)

AF:

0.0000336

AC:

AN:

59576

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.0000720

Hom.:

Bravo

AF:

0.0000491

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Jun 04, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Oct 12, 2021

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. -

not provided

Benign:2

Mar 04, 2024

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MET: BP4 -

Autosomal recessive nonsyndromic hearing loss 97

Uncertain:1

Oct 09, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Papillary renal cell carcinoma type 1;C2239176:Hepatocellular carcinoma;C4084709:Autosomal recessive nonsyndromic hearing loss 97;C4085248:Osteofibrous dysplasia;C5774205:Arthrogryposis, distal, IIa 11

Uncertain:1

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Hereditary papillary renal cell carcinoma

Uncertain:1

Mar 06, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Renal cell carcinoma

Benign:1

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Papillary renal cell carcinoma type 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

T;.;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

0.56

N;N;N

PhyloP100

5.7

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.10

N;N;N

REVEL

Benign

0.22

Sift

Benign

0.11

T;T;T

Sift4G

Benign

0.56

T;T;T

Polyphen

0.99

D;B;.

Vest4

0.15

MutPred

0.64

Loss of catalytic residue at V378 (P = 0.0331);Loss of catalytic residue at V378 (P = 0.0331);Loss of catalytic residue at V378 (P = 0.0331);

MVP

0.29

MPC

0.80

ClinPred

0.065

GERP RS

6.0

Varity_R

0.084

gMVP

0.49

Mutation Taster

=83/17

polymorphism

(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