chr7-116783353-G-A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_000245.4(MET):​c.3682G>A​(p.Asp1228Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1228Y) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

MET
NM_000245.4 missense

Scores

11
6
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 10.0

Publications

68 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
  • 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: PanelApp Australia, 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000245.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-116783353-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1734426.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.899
PP5
Variant 7-116783353-G-A is Pathogenic according to our data. Variant chr7-116783353-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13884.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
METNM_000245.4 linkc.3682G>A p.Asp1228Asn missense_variant Exon 19 of 21 ENST00000397752.8 NP_000236.2 P08581-1A0A024R759
METNM_001127500.3 linkc.3736G>A p.Asp1246Asn missense_variant Exon 19 of 21 NP_001120972.1 P08581-2A0A024R728
METNM_001324402.2 linkc.2392G>A p.Asp798Asn missense_variant Exon 18 of 20 NP_001311331.1 B4DLF5
METXM_011516223.2 linkc.3739G>A p.Asp1247Asn missense_variant Exon 20 of 22 XP_011514525.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
METENST00000397752.8 linkc.3682G>A p.Asp1228Asn missense_variant Exon 19 of 21 1 NM_000245.4 ENSP00000380860.3 P08581-1
METENST00000318493.11 linkc.3736G>A p.Asp1246Asn missense_variant Exon 19 of 21 1 ENSP00000317272.6 P08581-2
METENST00000436117.3 linkn.*1287G>A non_coding_transcript_exon_variant Exon 18 of 20 1 ENSP00000410980.2 P08581-3
METENST00000436117.3 linkn.*1287G>A 3_prime_UTR_variant Exon 18 of 20 1 ENSP00000410980.2 P08581-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Papillary renal cell carcinoma type 1 Pathogenic:1
May 01, 1997
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.85
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.030
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.85
D;.
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Pathogenic
0.90
D;D
MetaSVM
Uncertain
0.43
D
MutationAssessor
Benign
1.5
L;.
PhyloP100
10
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-4.4
D;D
REVEL
Pathogenic
0.72
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.81
MutPred
0.76
Loss of phosphorylation at Y1230 (P = 0.0828);.;
MVP
0.89
MPC
1.8
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.96
gMVP
0.89
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs121913671; hg19: chr7-116423407; COSMIC: COSV59256021; API