chr7-116771869-C-T

Position:

• chr7-116771869-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000245.4(MET):​c.2908C>T​(p.Arg970Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00458 in 1,613,774 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (17 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:2 B:20 O:1
• Conservation: PhyloP100: 3.57

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=0.009256214).
• BP6: Variant 7-116771869-C-T is Benign according to our data. Variant chr7-116771869-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 41623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-116771869-C-T is described in Lovd as [Likely_benign]. Variant chr7-116771869-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00312 (475/152220) while in subpopulation NFE AF= 0.00532 (362/68012). AF 95% confidence interval is 0.00487. There are 3 homozygotes in gnomad4. There are 209 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.2908C>T	p.Arg970Cys	missense_variant	14/21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.2962C>T	p.Arg988Cys	missense_variant	14/21		NP_001120972.1
MET	NM_001324402.2	c.1618C>T	p.Arg540Cys	missense_variant	13/20		NP_001311331.1
MET	XM_011516223.2	c.2965C>T	p.Arg989Cys	missense_variant	15/22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.2908C>T	p.Arg970Cys	missense_variant	14/21	1	NM_000245.4	ENSP00000380860	P3
MET	ENST00000318493.11	c.2962C>T	p.Arg988Cys	missense_variant	14/21	1		ENSP00000317272	A2
MET	ENST00000436117.3	c.*513C>T		3_prime_UTR_variant, NMD_transcript_variant	13/20	1		ENSP00000410980
MET	ENST00000454623.1	c.283+215C>T		intron_variant		5		ENSP00000398140

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 475 AN: 152102 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00158

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00532

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00288 AC: 717 AN: 248552 Hom.: 3 AF XY: 0.00297 AC XY: 400 AN XY: 134820

Gnomad AFR exome AF: 0.000904

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.000223

Gnomad SAS exome AF: 0.000654

Gnomad FIN exome AF: 0.000929

Gnomad NFE exome AF: 0.00520

Gnomad OTH exome AF: 0.00332

GnomAD4 exome AF: 0.00473 AC: 6915 AN: 1461554 Hom.: 17 Cov.: 32 AF XY: 0.00453 AC XY: 3291 AN XY: 727066

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000730

Gnomad4 FIN exome AF: 0.00124

Gnomad4 NFE exome AF: 0.00583

Gnomad4 OTH exome AF: 0.00283

GnomAD4 genome AF: 0.00312 AC: 475 AN: 152220 Hom.: 3 Cov.: 32 AF XY: 0.00281 AC XY: 209 AN XY: 74442

Gnomad4 AFR AF: 0.000867

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000943

Gnomad4 NFE AF: 0.00532

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00492 Hom.: 5

Bravo AF: 0.00328

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.000798 AC: 3

ESP6500EA AF: 0.00475 AC: 39

ExAC AF: 0.00284 AC: 343

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00720

EpiControl AF: 0.00569

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Uncertain:2 Benign:20 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:9

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Oct 06, 2023	BA1 based on allele frequency in NFE of 0.0050422 in gnomAD. PMID:20670955 variant lacks transforming ability. -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Feb 18, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MET: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2019	This variant is associated with the following publications: (PMID: 17322284, 17053076, 20670955, 25314153, 20368753, 23401458, 22128285, 25231402, 16734685, 25992381, 27626278, 28085233, 27636102, no PMID, 29970518, 14559814, 24728327, 23449277, 16189274, 15592501, 21847116, 15735036, 19723643, 26097886, 18564920, 22703879, 17404109, 23640142, 20370683, 20139696, 19037978, 18340114, 19318576, 17288874, 19861919, 17483355, 23662036, 19333071, 18709663, 20462834, 22838389, 20489150, 19393836, 21918175, 22530990, 25868855, 24327519, 24105670, 25416047, 24929890, 22973954, 26574927, 27153395, 28648934, 28116210, 27741505, 27899992, 28247034, 27013592, 28061464, 26934580, 27376238, 28603720, 28740441, 27923392, 28476232, 28619094, 31004003) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 24, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -

not specified Uncertain:1 Benign:3 Other:1

Uncertain significance, flagged submission	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gene associated with cancers, and variant has been identified in large B-cell lymphoma, but also pretty high frequency in ExAC with 1 homozygote, reported in apparently healthy individuals, and there are conflicting reports about functional impact (most recent functional study says no impact) -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
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	Genetic Services Laboratory, University of Chicago	May 04, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Papillary renal cell carcinoma type 1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jan 21, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 27, 2018	This alteration is classified as likely 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	Oct 23, 2020	- -

Neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Dec 26, 2014

- -

MET-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 07, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.092
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0093	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.79	N;N
REVEL	Benign	0.17
Sift	Uncertain	0.027	D;D
Sift4G	Benign	0.18	T;T
Polyphen		0.026	B;B
Vest4		0.37
MVP		0.66
MPC		0.35
ClinPred		0.19	T
GERP RS		4.9
Varity_R		0.27
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs34589476; hg19: chr7-116411923; COSMIC: COSV59257461; COSMIC: COSV59257461;