chr7-116695757-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000245.4(MET):c.-14-3314A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0477 in 490,252 control chromosomes in the GnomAD database, including 761 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: 𝑓 0.059 ( 341 hom., cov: 32)

Exomes 𝑓: 0.043 ( 420 hom. )

Consequence

MET
NM_000245.4 intron

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: -0.325

Publications

12 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027790964).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0937 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4 link	c.-14-3314A>T		intron_variant	Intron 1 of 20	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.-14-3314A>T		intron_variant	Intron 1 of 20	1	NM_000245.4	ENSP00000380860.3		P08581-1

Frequencies

GnomAD3 genomes

AF:

0.0586

AC:

8911

AN:

152164

Hom.:

335

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0959

Gnomad AMI

AF:

0.0515

Gnomad AMR

AF:

0.0796

Gnomad ASJ

AF:

0.0248

Gnomad EAS

AF:

0.0695

Gnomad SAS

AF:

0.0447

Gnomad FIN

AF:

0.00932

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0409

Gnomad OTH

AF:

0.0511

GnomAD2 exomes

AF:

0.0475

AC:

6981

AN:

147110

AF XY:

0.0460

show subpopulations

Gnomad AFR exome

AF:

0.0990

Gnomad AMR exome

AF:

0.0755

Gnomad ASJ exome

AF:

0.0248

Gnomad EAS exome

AF:

0.0672

Gnomad FIN exome

AF:

0.0103

Gnomad NFE exome

AF:

0.0432

Gnomad OTH exome

AF:

0.0453

GnomAD4 exome

AF:

0.0428

AC:

14458

AN:

337970

Hom.:

420

Cov.:

AF XY:

0.0426

AC XY:

8029

AN XY:

188650

show subpopulations

African (AFR)

AF:

0.101

AC:

927

AN:

9206

American (AMR)

AF:

0.0757

AC:

2078

AN:

27462

Ashkenazi Jewish (ASJ)

AF:

0.0244

AC:

296

AN:

12148

East Asian (EAS)

AF:

0.0666

AC:

944

AN:

14170

South Asian (SAS)

AF:

0.0393

AC:

2324

AN:

59198

European-Finnish (FIN)

AF:

0.0105

AC:

278

AN:

26588

Middle Eastern (MID)

AF:

0.0512

AC:

149

AN:

2910

European-Non Finnish (NFE)

AF:

0.0396

AC:

6749

AN:

170266

Other (OTH)

AF:

0.0445

AC:

713

AN:

16022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

551

1102

1653

2204

2755

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0587

AC:

8944

AN:

152282

Hom.:

341

Cov.:

AF XY:

0.0581

AC XY:

4323

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0962

AC:

3997

AN:

41544

American (AMR)

AF:

0.0794

AC:

1215

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0248

AC:

AN:

3470

East Asian (EAS)

AF:

0.0697

AC:

361

AN:

5180

South Asian (SAS)

AF:

0.0450

AC:

217

AN:

4824

European-Finnish (FIN)

AF:

0.00932

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0409

AC:

2783

AN:

68020

Other (OTH)

AF:

0.0549

AC:

116

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

429

859

1288

1718

2147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0461

Hom.:

Bravo

AF:

0.0647

TwinsUK

AF:

0.0472

AC:

175

ALSPAC

AF:

0.0446

AC:

172

ExAC

AF:

0.0354

AC:

687

Asia WGS

AF:

0.0710

AC:

247

AN:

3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.62

CADD

Benign

7.6

(source)

DANN

Benign

0.34

Eigen

Benign

-0.88

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.034

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.97

PhyloP100

-0.33

PROVEAN

Benign

0.0

REVEL

Benign

0.017

Sift

Pathogenic

0.0

MutPred

0.87

Loss of MoRF binding (P = 0.148);

ClinPred

0.0018

GERP RS

-2.0

Mutation Taster

=100/0

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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chr7-116695757-A-T

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