7-116700208-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000245.4(MET):c.1124A>G(p.Asn375Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.022 in 1,594,672 control chromosomes in the GnomAD database, including 630 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N375K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.019 (48 hom., cov: 33)
  • Exomes 𝑓: 0.022 (582 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: 2.92

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023828745).
• BP6: Variant 7-116700208-A-G is Benign according to our data. Variant chr7-116700208-A-G is described in ClinVar as [Benign]. Clinvar id is 41611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-116700208-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MET	NM_000245.4	c.1124A>G	p.Asn375Ser	missense_variant	2/21	ENST00000397752.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MET	ENST00000397752.8	c.1124A>G	p.Asn375Ser	missense_variant	2/21	1	NM_000245.4	P3
MET	ENST00000318493.11	c.1124A>G	p.Asn375Ser	missense_variant	2/21	1		A2
MET	ENST00000436117.3	c.1124A>G	p.Asn375Ser	missense_variant, NMD_transcript_variant	2/20	1
MET	ENST00000422097.2	c.1124A>G	p.Asn375Ser	missense_variant	2/12	3

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2953 AN: 152194 Hom.: 49 Cov.: 33

Gnomad AFR AF: 0.00702

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.00871

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.0624

Gnomad SAS AF: 0.0724

Gnomad FIN AF: 0.0446

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0270 AC: 6190 AN: 228932 Hom.: 184 AF XY: 0.0294 AC XY: 3642 AN XY: 123884

Gnomad AFR exome AF: 0.00646

Gnomad AMR exome AF: 0.00613

Gnomad ASJ exome AF: 0.00315

Gnomad EAS exome AF: 0.0668

Gnomad SAS exome AF: 0.0741

Gnomad FIN exome AF: 0.0409

Gnomad NFE exome AF: 0.0179

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0223 AC: 32104 AN: 1442360 Hom.: 582 Cov.: 32 AF XY: 0.0237 AC XY: 16953 AN XY: 716604

Gnomad4 AFR exome AF: 0.00510

Gnomad4 AMR exome AF: 0.00641

Gnomad4 ASJ exome AF: 0.00329

Gnomad4 EAS exome AF: 0.0508

Gnomad4 SAS exome AF: 0.0693

Gnomad4 FIN exome AF: 0.0402

Gnomad4 NFE exome AF: 0.0185

Gnomad4 OTH exome AF: 0.0223

GnomAD4 genome AF: 0.0194 AC: 2949 AN: 152312 Hom.: 48 Cov.: 33 AF XY: 0.0212 AC XY: 1577 AN XY: 74472

Gnomad4 AFR AF: 0.00697

Gnomad4 AMR AF: 0.00870

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.0621

Gnomad4 SAS AF: 0.0721

Gnomad4 FIN AF: 0.0446

Gnomad4 NFE AF: 0.0192

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0183 Hom.: 65

Bravo AF: 0.0145

TwinsUK AF: 0.0165 AC: 61

ALSPAC AF: 0.0179 AC: 69

ESP6500AA AF: 0.00675 AC: 26

ESP6500EA AF: 0.0182 AC: 151

ExAC AF: 0.0278 AC: 3356

Asia WGS AF: 0.0700 AC: 244 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7 Other:1

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 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. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 05, 2018	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2016	Variant summary: The c.1124A>G (p.Asn375Ser) in MET gene is a missense change that involves a non-conserved nucleotide and 3/4 in silico tools predict benign outcome. The variant is present in the control population dataset of ExAC at an overall frequency 0.028 (3293/116530 chrs tested) including 105 homozygotes. This frequency exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.0000015). The variant has not, to our knowledge, been reported in affected individuals, but is cited as Benign by a multiple reputable databases/clinical laboratories. Taking together, the variant was classified as Benign. -

Papillary renal cell carcinoma type 1 Benign:2

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

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 28, 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 11, 2021	- -

Renal cell carcinoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.37	T;.;.
Eigen	Benign	-0.011
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;D;D
MetaRNN	Benign	0.0024	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	L;L;L
MutationTaster	Benign	0.54	D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.096	T;T;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.043	B;B;.
Vest4		0.11
MPC		0.37
ClinPred		0.010	T
GERP RS		4.9
Varity_R		0.17
gMVP		0.41

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

Other links and lift over

dbSNP: rs33917957; hg19: chr7-116340262; COSMIC: COSV59260365; COSMIC: COSV59260365;