rs13223756

chr7-116757518-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000245.4(MET):c.1944A>G(p.Gln648=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.17

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]

ACMG classification

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/exons	MANE	UniProt
MET	NM_000245.4	c.1944A>G	p.Gln648=	synonymous_variant	7/21	ENST00000397752.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MET	ENST00000397752.8	c.1944A>G	p.Gln648=	synonymous_variant	7/21	1	NM_000245.4	P3
MET	ENST00000318493.11	c.1944A>G	p.Gln648=	synonymous_variant	7/21	1		A2
MET	ENST00000436117.3	c.1944A>G	p.Gln648=	synonymous_variant, NMD_transcript_variant	7/20	1
MET	ENST00000422097.2	c.1944A>G	p.Gln648=	synonymous_variant	7/12	3

Frequencies

GnomAD3 genomes AF: 0.171 AC: 26008 AN: 152034 Hom.: 2342 Cov.: 32

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

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

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

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 12, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Papillary renal cell carcinoma type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Renal cell carcinoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2016

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. -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 24, 2014

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

Other links and lift over

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