7-116757518-A-G

Variant names:

• chr7-116757518-A-G
• rs13223756
• NM_000245.4:c.1944A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.17
• Publications: 30 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 93569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000245.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	NM_000245.4	MANE Select	c.1944A>G	p.Gln648Gln	synonymous	Exon 7 of 21	NP_000236.2
	MET	NM_001127500.3		c.1944A>G	p.Gln648Gln	synonymous	Exon 7 of 21	NP_001120972.1
	MET	NM_001324402.2		c.654A>G	p.Gln218Gln	synonymous	Exon 6 of 20	NP_001311331.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	ENST00000397752.8	TSL:1 MANE Select	c.1944A>G	p.Gln648Gln	synonymous	Exon 7 of 21	ENSP00000380860.3
	MET	ENST00000318493.11	TSL:1	c.1944A>G	p.Gln648Gln	synonymous	Exon 7 of 21	ENSP00000317272.6
	MET	ENST00000436117.3	TSL:1	n.1944A>G		non_coding_transcript_exon	Exon 7 of 20	ENSP00000410980.2

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

GnomAD2 exomes AF: 0.182 AC: 45494 AN: 249296 AF XY: 0.188

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 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

African (AFR) AF: 0.126 AC: 4198 AN: 33444

American (AMR) AF: 0.0848 AC: 3792 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 5130 AN: 26118

East Asian (EAS) AF: 0.272 AC: 10768 AN: 39660

South Asian (SAS) AF: 0.227 AC: 19540 AN: 86222

European-Finnish (FIN) AF: 0.191 AC: 10209 AN: 53394

Middle Eastern (MID) AF: 0.146 AC: 842 AN: 5750

European-Non Finnish (NFE) AF: 0.191 AC: 212536 AN: 1111196

Other (OTH) AF: 0.187 AC: 11282 AN: 60356

GnomAD4 genome AF: 0.171 AC: 26013 AN: 152152 Hom.: 2341 Cov.: 32 AF XY: 0.171 AC XY: 12756 AN XY: 74380

African (AFR) AF: 0.129 AC: 5369 AN: 41520

American (AMR) AF: 0.125 AC: 1911 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 738 AN: 3470

East Asian (EAS) AF: 0.284 AC: 1467 AN: 5166

South Asian (SAS) AF: 0.230 AC: 1107 AN: 4818

European-Finnish (FIN) AF: 0.194 AC: 2050 AN: 10584

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.187 AC: 12687 AN: 67998

Other (OTH) AF: 0.159 AC: 335 AN: 2108

Alfa AF: 0.179 Hom.: 5625

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

Submissions by phenotype

not specified Benign:5

Jul 12, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

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.

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Papillary renal cell carcinoma type 1 Benign:3

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.

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.

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

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.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.29
DANN	Benign	0.25
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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