7-116700215-C-T

Position:

• chr7-116700215-C-T

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.1131C>T​(p.Ile377Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,594,374 control chromosomes in the GnomAD database, including 1,605 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (846 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (759 hom.)
• Consequence: MET NM_000245.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.288

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=-0.51).
• BP6: Variant 7-116700215-C-T is Benign according to our data. Variant chr7-116700215-C-T is described in ClinVar as [Benign]. Clinvar id is 93566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-116700215-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.288 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.1131C>T	p.Ile377Ile	synonymous_variant	2/21	ENST00000397752.8	NP_000236.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.1131C>T	p.Ile377Ile	synonymous_variant	2/21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.1131C>T	p.Ile377Ile	synonymous_variant	2/21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.1131C>T		non_coding_transcript_exon_variant	2/20	1		ENSP00000410980.2
MET	ENST00000422097.2	c.1131C>T	p.Ile377Ile	synonymous_variant	2/12	3		ENSP00000398776.2

Frequencies

GnomAD3 genomes AF: 0.0573 AC: 8714 AN: 152074 Hom.: 844 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.0412

GnomAD3 exomes AF: 0.0157 AC: 3588 AN: 228660 Hom.: 348 AF XY: 0.0119 AC XY: 1469 AN XY: 123838

Gnomad AFR exome AF: 0.206

Gnomad AMR exome AF: 0.00765

Gnomad ASJ exome AF: 0.00849

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000912

Gnomad FIN exome AF: 0.0000484

Gnomad NFE exome AF: 0.000963

Gnomad OTH exome AF: 0.00719

GnomAD4 exome AF: 0.00628 AC: 9050 AN: 1442184 Hom.: 759 Cov.: 32 AF XY: 0.00545 AC XY: 3909 AN XY: 716616

Gnomad4 AFR exome AF: 0.209

Gnomad4 AMR exome AF: 0.00895

Gnomad4 ASJ exome AF: 0.00935

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.000920

Gnomad4 FIN exome AF: 0.0000379

Gnomad4 NFE exome AF: 0.000586

Gnomad4 OTH exome AF: 0.0140

GnomAD4 genome AF: 0.0574 AC: 8729 AN: 152190 Hom.: 846 Cov.: 32 AF XY: 0.0557 AC XY: 4146 AN XY: 74398

Gnomad4 AFR AF: 0.199

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000912

Gnomad4 OTH AF: 0.0408

Alfa AF: 0.0222 Hom.: 175

Bravo AF: 0.0649

Asia WGS AF: 0.0100 AC: 37 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 26, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 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 Benign:5

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 28, 2022	- -
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.1131C>T (p.Ile377Ile) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SRp40. This variant was found in 2192/116598 control chromosomes (215 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.2046621 (1993/9738). This frequency is about 136441 times the estimated maximal expected allele frequency of a pathogenic MET variant (0.0000015), suggesting this is a common benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

Papillary renal cell carcinoma type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 21, 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 19, 2021	- -

Renal cell carcinoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.49
DANN	Benign	0.82

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: rs28444388; hg19: chr7-116340269; COSMIC: COSV59258618; COSMIC: COSV59258618;