rs749738523

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_000245.4(MET):​c.1132G>A​(p.Val378Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000407 in 1,596,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

MET
NM_000245.4 missense

Scores

6
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 5.73
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 Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.18482578).
BP6
Variant 7-116700216-G-A is Benign according to our data. Variant chr7-116700216-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188364.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=2}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000394 (6/152142) while in subpopulation NFE AF= 0.0000735 (5/68008). AF 95% confidence interval is 0.0000285. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
METNM_000245.4 linkc.1132G>A p.Val378Ile missense_variant Exon 2 of 21 ENST00000397752.8 NP_000236.2 P08581-1A0A024R759

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
METENST00000397752.8 linkc.1132G>A p.Val378Ile missense_variant Exon 2 of 21 1 NM_000245.4 ENSP00000380860.3 P08581-1
METENST00000318493.11 linkc.1132G>A p.Val378Ile missense_variant Exon 2 of 21 1 ENSP00000317272.6 P08581-2
METENST00000436117.3 linkn.1132G>A non_coding_transcript_exon_variant Exon 2 of 20 1 ENSP00000410980.2 P08581-3
METENST00000422097.2 linkc.1132G>A p.Val378Ile missense_variant Exon 2 of 12 3 ENSP00000398776.2 H7C174

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152142
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000433
AC:
10
AN:
230896
Hom.:
0
AF XY:
0.0000640
AC XY:
8
AN XY:
125022
show subpopulations
Gnomad AFR exome
AF:
0.0000658
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000585
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000651
Gnomad OTH exome
AF:
0.000182
GnomAD4 exome
AF:
0.0000409
AC:
59
AN:
1443950
Hom.:
0
Cov.:
32
AF XY:
0.0000390
AC XY:
28
AN XY:
717536
show subpopulations
Gnomad4 AFR exome
AF:
0.0000309
Gnomad4 AMR exome
AF:
0.0000248
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000151
Gnomad4 SAS exome
AF:
0.0000610
Gnomad4 FIN exome
AF:
0.0000947
Gnomad4 NFE exome
AF:
0.0000343
Gnomad4 OTH exome
AF:
0.0000336
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152142
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74314
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000892
Hom.:
0
Bravo
AF:
0.0000491
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000331
AC:
4

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Jun 04, 2021
Sema4, Sema4
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Oct 12, 2021
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:2
Mar 04, 2024
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Oct 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

MET: BP4 -

Autosomal recessive nonsyndromic hearing loss 97 Uncertain:1
Oct 09, 2023
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Renal cell carcinoma Benign:1
Oct 30, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Papillary renal cell carcinoma type 1 Benign:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.093
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.22
T;.;.
Eigen
Uncertain
0.38
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Uncertain
0.88
D;D;D
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.18
T;T;T
MetaSVM
Benign
-1.2
T
MutationAssessor
Benign
0.56
N;N;N
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-0.10
N;N;N
REVEL
Benign
0.22
Sift
Benign
0.11
T;T;T
Sift4G
Benign
0.56
T;T;T
Polyphen
0.99
D;B;.
Vest4
0.15
MutPred
0.64
Loss of catalytic residue at V378 (P = 0.0331);Loss of catalytic residue at V378 (P = 0.0331);Loss of catalytic residue at V378 (P = 0.0331);
MVP
0.29
MPC
0.80
ClinPred
0.065
T
GERP RS
6.0
Varity_R
0.084
gMVP
0.49

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

LitVar

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

Other links and lift over

dbSNP: rs749738523; hg19: chr7-116340270; COSMIC: COSV59263129; COSMIC: COSV59263129; API