Genetic Variant NM_000245.4:c.4092G>A (chr7-116796043-G-A) – ACMG Classification: Benign (-19 pts)

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: 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 -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.

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.4092G>A	p.Pro1364Pro	synonymous	Exon 21 of 21	NP_000236.2
MET	NM_001127500.3		c.4146G>A	p.Pro1382Pro	synonymous	Exon 21 of 21	NP_001120972.1	P08581-2
MET	NM_001324402.2		c.2802G>A	p.Pro934Pro	synonymous	Exon 20 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.4092G>A	p.Pro1364Pro	synonymous	Exon 21 of 21	ENSP00000380860.3	P08581-1
MET	ENST00000318493.11	TSL:1	c.4146G>A	p.Pro1382Pro	synonymous	Exon 21 of 21	ENSP00000317272.6	P08581-2
MET	ENST00000436117.3	TSL:1	n.*1697G>A		non_coding_transcript_exon	Exon 20 of 20	ENSP00000410980.2	P08581-3

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

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 (3)

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

-0.33

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

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