7-116757518-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000245.4(MET):​c.1944A>G​(p.Gln648Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,612,994 control chromosomes in the GnomAD database, including 29,894 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2341 hom., cov: 32)
Exomes 𝑓: 0.19 ( 27553 hom. )

Consequence

MET
NM_000245.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -1.17
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 -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant 7-116757518-A-G is Benign according to our data. Variant chr7-116757518-A-G is described in ClinVar as [Benign]. Clinvar id is 93569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-116757518-A-G is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-1.17 with no splicing effect.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
METNM_000245.4 linkc.1944A>G p.Gln648Gln synonymous_variant Exon 7 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.1944A>G p.Gln648Gln synonymous_variant Exon 7 of 21 1 NM_000245.4 ENSP00000380860.3 P08581-1
METENST00000318493.11 linkc.1944A>G p.Gln648Gln synonymous_variant Exon 7 of 21 1 ENSP00000317272.6 P08581-2
METENST00000436117.3 linkn.1944A>G non_coding_transcript_exon_variant Exon 7 of 20 1 ENSP00000410980.2 P08581-3
METENST00000422097.2 linkc.1944A>G p.Gln648Gln synonymous_variant Exon 7 of 12 3 ENSP00000398776.2 H7C174

Frequencies

GnomAD3 genomes
AF:
0.171
AC:
26008
AN:
152034
Hom.:
2342
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.129
Gnomad AMI
AF:
0.332
Gnomad AMR
AF:
0.125
Gnomad ASJ
AF:
0.213
Gnomad EAS
AF:
0.283
Gnomad SAS
AF:
0.230
Gnomad FIN
AF:
0.194
Gnomad MID
AF:
0.155
Gnomad NFE
AF:
0.187
Gnomad OTH
AF:
0.158
GnomAD3 exomes
AF:
0.182
AC:
45494
AN:
249296
Hom.:
4535
AF XY:
0.188
AC XY:
25453
AN XY:
135246
show subpopulations
Gnomad AFR exome
AF:
0.125
Gnomad AMR exome
AF:
0.0804
Gnomad ASJ exome
AF:
0.196
Gnomad EAS exome
AF:
0.294
Gnomad SAS exome
AF:
0.231
Gnomad FIN exome
AF:
0.187
Gnomad NFE exome
AF:
0.189
Gnomad OTH exome
AF:
0.177
GnomAD4 exome
AF:
0.191
AC:
278297
AN:
1460842
Hom.:
27553
Cov.:
33
AF XY:
0.193
AC XY:
139975
AN XY:
726788
show subpopulations
Gnomad4 AFR exome
AF:
0.126
Gnomad4 AMR exome
AF:
0.0848
Gnomad4 ASJ exome
AF:
0.196
Gnomad4 EAS exome
AF:
0.272
Gnomad4 SAS exome
AF:
0.227
Gnomad4 FIN exome
AF:
0.191
Gnomad4 NFE exome
AF:
0.191
Gnomad4 OTH exome
AF:
0.187
GnomAD4 genome
AF:
0.171
AC:
26013
AN:
152152
Hom.:
2341
Cov.:
32
AF XY:
0.171
AC XY:
12756
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.129
Gnomad4 AMR
AF:
0.125
Gnomad4 ASJ
AF:
0.213
Gnomad4 EAS
AF:
0.284
Gnomad4 SAS
AF:
0.230
Gnomad4 FIN
AF:
0.194
Gnomad4 NFE
AF:
0.187
Gnomad4 OTH
AF:
0.159
Alfa
AF:
0.181
Hom.:
4341
Bravo
AF:
0.162
Asia WGS
AF:
0.251
AC:
873
AN:
3478
EpiCase
AF:
0.180
EpiControl
AF:
0.186

ClinVar

Significance: Benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 12, 2013
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 09, 2016
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Papillary renal cell carcinoma type 1 Benign:3
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 08, 2024
Myriad Genetics, Inc.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Aug 18, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The MET c.1944A>G (p.Gln648Gln) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools predicting no significant impact on splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 22638/120534 (1/5, 2318 homozygotes), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic MET variant of 1/666666, suggesting this variant is likely a benign polymorphism. Multiple reputable clinical laboratories have cited the variant as "benign." Therefore, the variant of interest has been classified as Benign. -

Renal cell carcinoma Benign:1
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1
Oct 24, 2014
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
CADD
Benign
0.29
DANN
Benign
0.25

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

LitVar

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

Other links and lift over

dbSNP: rs13223756; hg19: chr7-116397572; COSMIC: COSV59257388; COSMIC: COSV59257388; API