rs6566

chr7-116798364-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_000245.4(MET):c.*2240G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 187,378 control chromosomes in the GnomAD database, including 14,814 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (11175 hom., cov: 32)
  • Exomes 𝑓: 0.45 (3639 hom.)
• Consequence: MET NM_000245.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.505

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 7-116798364-G-A is Benign according to our data. Variant chr7-116798364-G-A is described in ClinVar as [Benign]. Clinvar id is 358730.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-116798364-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MET	NM_000245.4	c.*2240G>A		3_prime_UTR_variant	21/21	ENST00000397752.8
MET	NM_001127500.3	c.*2240G>A		3_prime_UTR_variant	21/21
MET	NM_001324402.2	c.*2240G>A		3_prime_UTR_variant	20/20
MET	XM_011516223.2	c.*2240G>A		3_prime_UTR_variant	22/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MET	ENST00000397752.8	c.*2240G>A		3_prime_UTR_variant	21/21	1	NM_000245.4	P3
MET	ENST00000318493.11	c.*2240G>A		3_prime_UTR_variant	21/21	1		A2
MET	ENST00000436117.3	c.*4018G>A		3_prime_UTR_variant, NMD_transcript_variant	20/20	1

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53445 AN: 151974 Hom.: 11188 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.457

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.393

GnomAD4 exome AF: 0.450 AC: 15879 AN: 35286 Hom.: 3639 Cov.: 0 AF XY: 0.456 AC XY: 7452 AN XY: 16352

Gnomad4 AFR exome AF: 0.0989

Gnomad4 AMR exome AF: 0.470

Gnomad4 ASJ exome AF: 0.501

Gnomad4 EAS exome AF: 0.509

Gnomad4 SAS exome AF: 0.472

Gnomad4 FIN exome AF: 0.401

Gnomad4 NFE exome AF: 0.454

Gnomad4 OTH exome AF: 0.412

GnomAD4 genome AF: 0.351 AC: 53419 AN: 152092 Hom.: 11175 Cov.: 32 AF XY: 0.353 AC XY: 26275 AN XY: 74330

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.445

Gnomad4 ASJ AF: 0.487

Gnomad4 EAS AF: 0.471

Gnomad4 SAS AF: 0.455

Gnomad4 FIN AF: 0.383

Gnomad4 NFE AF: 0.451

Gnomad4 OTH AF: 0.388

Alfa AF: 0.435 Hom.: 15334

Bravo AF: 0.346

Asia WGS AF: 0.415 AC: 1442 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Papillary renal cell carcinoma type 1 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	12
Dann	Benign	0.70

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: rs6566; hg19: chr7-116438418; COSMIC: COSV59266573; COSMIC: COSV59266573;