dbSNP rs34589476: MET:p.Arg970Cys (chr7-116771869-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000245.4(MET):c.2908C>T(p.Arg970Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00458 in 1,613,774 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. R970H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0031 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 17 hom. )

Consequence

MET
NM_000245.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:23O:1

Conservation

PhyloP100: 3.57

Publications

72 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009256214).

BP6

Variant 7-116771869-C-T is Benign according to our data. Variant chr7-116771869-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41623.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00312 (475/152220) while in subpopulation NFE AF = 0.00532 (362/68012). AF 95% confidence interval is 0.00487. There are 3 homozygotes in GnomAd4. There are 209 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR,Unknown gene

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.2908C>T	p.Arg970Cys	missense	Exon 14 of 21	NP_000236.2
MET	NM_001127500.3		c.2962C>T	p.Arg988Cys	missense	Exon 14 of 21	NP_001120972.1	P08581-2
MET	NM_001324402.2		c.1618C>T	p.Arg540Cys	missense	Exon 13 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.2908C>T	p.Arg970Cys	missense	Exon 14 of 21	ENSP00000380860.3	P08581-1
MET	ENST00000318493.11	TSL:1	c.2962C>T	p.Arg988Cys	missense	Exon 14 of 21	ENSP00000317272.6	P08581-2
MET	ENST00000436117.3	TSL:1	n.*513C>T		non_coding_transcript_exon	Exon 13 of 20	ENSP00000410980.2	P08581-3

Frequencies

GnomAD3 genomes

AF:

0.00312

AC:

475

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.00158

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00532

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00288

AC:

717

AN:

248552

AF XY:

0.00297

show subpopulations

Gnomad AFR exome

AF:

0.000904

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.000223

Gnomad FIN exome

AF:

0.000929

Gnomad NFE exome

AF:

0.00520

Gnomad OTH exome

AF:

0.00332

GnomAD4 exome

AF:

0.00473

AC:

6915

AN:

1461554

Hom.:

Cov.:

AF XY:

0.00453

AC XY:

3291

AN XY:

727066

show subpopulations

African (AFR)

AF:

0.000986

AC:

AN:

33460

American (AMR)

AF:

0.00123

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00145

AC:

AN:

26126

East Asian (EAS)

AF:

0.000101

AC:

AN:

39666

South Asian (SAS)

AF:

0.000730

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00124

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00583

AC:

6478

AN:

1111810

Other (OTH)

AF:

0.00283

AC:

171

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

408

815

1223

1630

2038

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

232

464

696

928

1160

<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:

0.00312

AC:

475

AN:

152220

Hom.:

Cov.:

AF XY:

0.00281

AC XY:

209

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.000867

AC:

AN:

41546

American (AMR)

AF:

0.00157

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000943

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00532

AC:

362

AN:

68012

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00459

Hom.:

Bravo

AF:

0.00328

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.000798

AC:

ESP6500EA

AF:

0.00475

AC:

ExAC

AF:

0.00284

AC:

343

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00720

EpiControl

AF:

0.00569

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (10)

not specified (6)

Papillary renal cell carcinoma type 1 (5)

Hereditary cancer-predisposing syndrome (2)

MET-related disorder (1)

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

Renal cell carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

Eigen

Benign

-0.11

Eigen_PC

Benign

0.092

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.023

MetaRNN

Benign

0.0093

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.0

PhyloP100

3.6

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.79

REVEL

Benign

0.17

Sift

Uncertain

0.027

Sift4G

Benign

0.18

Polyphen

0.026

Vest4

0.37

MVP

0.66

MPC

0.35

ClinPred

0.19

GERP RS

4.9

Varity_R

0.27

gMVP

0.61

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over