rs1554400071

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000245.4(MET):​c.3524A>C​(p.Asn1175Thr) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

MET
NM_000245.4 missense, splice_region

Scores

1
7
11
Splicing: ADA: 0.0002582
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.29
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1
In a domain Protein kinase (size 267) in uniprot entity MET_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) in NM_000245.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.23703215).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
METNM_000245.4 linkuse as main transcriptc.3524A>C p.Asn1175Thr missense_variant, splice_region_variant 18/21 ENST00000397752.8 NP_000236.2 P08581-1A0A024R759
METNM_001127500.3 linkuse as main transcriptc.3578A>C p.Asn1193Thr missense_variant, splice_region_variant 18/21 NP_001120972.1 P08581-2A0A024R728
METNM_001324402.2 linkuse as main transcriptc.2234A>C p.Asn745Thr missense_variant, splice_region_variant 17/20 NP_001311331.1 B4DLF5
METXM_011516223.2 linkuse as main transcriptc.3581A>C p.Asn1194Thr missense_variant, splice_region_variant 19/22 XP_011514525.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
METENST00000397752.8 linkuse as main transcriptc.3524A>C p.Asn1175Thr missense_variant, splice_region_variant 18/211 NM_000245.4 ENSP00000380860.3 P08581-1
METENST00000318493.11 linkuse as main transcriptc.3578A>C p.Asn1193Thr missense_variant, splice_region_variant 18/211 ENSP00000317272.6 P08581-2
METENST00000436117.3 linkuse as main transcriptn.*1129A>C splice_region_variant, non_coding_transcript_exon_variant 17/201 ENSP00000410980.2 P08581-3
METENST00000436117.3 linkuse as main transcriptn.*1129A>C 3_prime_UTR_variant 17/201 ENSP00000410980.2 P08581-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Renal cell carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 21, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 454243). This variant has not been reported in the literature in individuals affected with MET-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 1193 of the MET protein (p.Asn1193Thr). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Benign
-0.0063
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
22
DANN
Benign
0.97
DEOGEN2
Uncertain
0.78
D;.
Eigen
Benign
-0.032
Eigen_PC
Benign
0.078
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.89
D;D
M_CAP
Benign
0.060
D
MetaRNN
Benign
0.24
T;T
MetaSVM
Benign
-0.49
T
MutationAssessor
Benign
0.73
N;.
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-4.5
D;D
REVEL
Uncertain
0.32
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.0060
D;D
Polyphen
0.56
P;B
Vest4
0.41
MutPred
0.40
Gain of phosphorylation at N1175 (P = 0.0909);.;
MVP
0.78
MPC
1.1
ClinPred
0.90
D
GERP RS
2.2
Varity_R
0.77
gMVP
0.67

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00026
dbscSNV1_RF
Benign
0.022
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554400071; hg19: chr7-116422043; API