rs77523018

chr7-116700169-T-C

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.1085T>C(p.Met362Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,595,714 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. M362V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0069 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (12 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 7.67

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=0.015252113).
• BP6: Variant 7-116700169-T-C is Benign according to our data. Variant chr7-116700169-T-C is described in ClinVar as [Benign]. Clinvar id is 93565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-116700169-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0069 (1051/152318) while in subpopulation AFR AF= 0.0237 (986/41572). AF 95% confidence interval is 0.0225. There are 15 homozygotes in gnomad4. There are 488 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MET	NM_000245.4	c.1085T>C	p.Met362Thr	missense_variant	2/21	ENST00000397752.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MET	ENST00000397752.8	c.1085T>C	p.Met362Thr	missense_variant	2/21	1	NM_000245.4	P3
MET	ENST00000318493.11	c.1085T>C	p.Met362Thr	missense_variant	2/21	1		A2
MET	ENST00000436117.3	c.1085T>C	p.Met362Thr	missense_variant, NMD_transcript_variant	2/20	1
MET	ENST00000422097.2	c.1085T>C	p.Met362Thr	missense_variant	2/12	3

Frequencies

GnomAD3 genomes AF: 0.00691 AC: 1051 AN: 152200 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0238

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00165 AC: 384 AN: 232778 Hom.: 5 AF XY: 0.00116 AC XY: 146 AN XY: 125664

Gnomad AFR exome AF: 0.0214

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000834

Gnomad OTH exome AF: 0.000903

GnomAD4 exome AF: 0.000687 AC: 992 AN: 1443396 Hom.: 12 Cov.: 32 AF XY: 0.000585 AC XY: 419 AN XY: 716334

Gnomad4 AFR exome AF: 0.0239

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000608

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000507

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.00690 AC: 1051 AN: 152318 Hom.: 15 Cov.: 32 AF XY: 0.00655 AC XY: 488 AN XY: 74484

Gnomad4 AFR AF: 0.0237

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00135 Hom.: 4

Bravo AF: 0.00750

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0211 AC: 82

ESP6500EA AF: 0.000241 AC: 2

ExAC AF: 0.00191 AC: 231

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6 Other:1

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2018	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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic 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	Eurofins Ntd Llc (ga)	Feb 18, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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 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. -

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

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 19, 2020

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2015

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
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	23
Dann	Benign	0.97
DEOGEN2	Benign	0.37	T;.;.
Eigen	Benign	0.050
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T;T;T
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L;L
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.0040	B;B;.
Vest4		0.37
MVP		0.18
MPC		0.29
ClinPred		0.036	T
GERP RS		6.0
Varity_R		0.44
gMVP		0.73

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: rs77523018; hg19: chr7-116340223; COSMIC: COSV59270394; COSMIC: COSV59270394;