Genetic Variant MET:p.Asp1286Asp (chr7-116795714-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000245.4(MET):c.3858C>T(p.Asp1286Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 1,613,762 control chromosomes in the GnomAD database, including 156,030 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 11009 hom., cov: 31)

Exomes 𝑓: 0.44 ( 145021 hom. )

Consequence

MET
NM_000245.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: -2.04

Publications

50 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
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: 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 7-116795714-C-T is Benign according to our data. Variant chr7-116795714-C-T is described in ClinVar as Benign. ClinVar VariationId is 93574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.04 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000245.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MET	NM_000245.4	MANE Select	c.3858C>T	p.Asp1286Asp	synonymous	Exon 20 of 21	NP_000236.2
MET	NM_001127500.3		c.3912C>T	p.Asp1304Asp	synonymous	Exon 20 of 21	NP_001120972.1	P08581-2
MET	NM_001324402.2		c.2568C>T	p.Asp856Asp	synonymous	Exon 19 of 20	NP_001311331.1	B4DLF5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MET	ENST00000397752.8	TSL:1 MANE Select	c.3858C>T	p.Asp1286Asp	synonymous	Exon 20 of 21	ENSP00000380860.3	P08581-1
MET	ENST00000318493.11	TSL:1	c.3912C>T	p.Asp1304Asp	synonymous	Exon 20 of 21	ENSP00000317272.6	P08581-2
MET	ENST00000436117.3	TSL:1	n.*1463C>T		non_coding_transcript_exon	Exon 19 of 20	ENSP00000410980.2	P08581-3

Frequencies

GnomAD3 genomes

AF:

0.348

AC:

52907

AN:

151856

Hom.:

11022

Cov.:

show subpopulations

Gnomad AFR

AF:

0.100

Gnomad AMI

AF:

0.305

Gnomad AMR

AF:

0.443

Gnomad ASJ

AF:

0.487

Gnomad EAS

AF:

0.469

Gnomad SAS

AF:

0.455

Gnomad FIN

AF:

0.382

Gnomad MID

AF:

0.430

Gnomad NFE

AF:

0.448

Gnomad OTH

AF:

0.389

GnomAD2 exomes

AF:

0.433

AC:

107988

AN:

249486

AF XY:

0.435

show subpopulations

Gnomad AFR exome

AF:

0.0896

Gnomad AMR exome

AF:

0.518

Gnomad ASJ exome

AF:

0.487

Gnomad EAS exome

AF:

0.460

Gnomad FIN exome

AF:

0.394

Gnomad NFE exome

AF:

0.444

Gnomad OTH exome

AF:

0.455

GnomAD4 exome

AF:

0.441

AC:

644758

AN:

1461788

Hom.:

145021

Cov.:

AF XY:

0.442

AC XY:

321615

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.0870

AC:

2912

AN:

33478

American (AMR)

AF:

0.510

AC:

22802

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.490

AC:

12816

AN:

26132

East Asian (EAS)

AF:

0.490

AC:

19437

AN:

39698

South Asian (SAS)

AF:

0.452

AC:

39026

AN:

86254

European-Finnish (FIN)

AF:

0.399

AC:

21330

AN:

53420

Middle Eastern (MID)

AF:

0.427

AC:

2456

AN:

5756

European-Non Finnish (NFE)

AF:

0.447

AC:

497526

AN:

1111930

Other (OTH)

AF:

0.438

AC:

26453

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

23729

47458

71187

94916

118645

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14942

29884

44826

59768

74710

<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:

0.348

AC:

52883

AN:

151974

Hom.:

11009

Cov.:

AF XY:

0.351

AC XY:

26035

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.100

AC:

4154

AN:

41460

American (AMR)

AF:

0.443

AC:

6762

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.487

AC:

1689

AN:

3466

East Asian (EAS)

AF:

0.470

AC:

2424

AN:

5162

South Asian (SAS)

AF:

0.454

AC:

2186

AN:

4820

European-Finnish (FIN)

AF:

0.382

AC:

4026

AN:

10548

Middle Eastern (MID)

AF:

0.412

AC:

121

AN:

294

European-Non Finnish (NFE)

AF:

0.448

AC:

30431

AN:

67944

Other (OTH)

AF:

0.384

AC:

812

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1560

3120

4681

6241

7801

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

518

1036

1554

2072

2590

<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:

0.419

Hom.:

23098

Bravo

AF:

0.343

Asia WGS

AF:

0.415

AC:

1442

AN:

3478

EpiCase

AF:

0.448

EpiControl

AF:

0.447

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Papillary renal cell carcinoma type 1 (4)

Hereditary cancer-predisposing syndrome (2)

not provided (2)

Autosomal recessive nonsyndromic hearing loss 97 (1)

Renal cell carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.050

(source)

DANN

Benign

0.42

PhyloP100

-2.0

Mutation Taster

=98/2

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over