rs1621

Positions:

• chr7-116797552-G-A
• chr7-116797552-G-C

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.*1428G>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 0.66 in 227,786 control chromosomes in the GnomAD database, including 50,325 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31873 hom., cov: 31)
  • Exomes 𝑓: 0.69 (18452 hom.)
• Consequence: MET NM_000245.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.54

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 (BayesDel_noAF=-0.6).
• BP6: Variant 7-116797552-G-A is Benign according to our data. Variant chr7-116797552-G-A is described in ClinVar as [Benign]. Clinvar id is 358717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.848 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MET	NM_000245.4	c.*1428G>A		3_prime_UTR_variant	21/21	ENST00000397752.8
MET	NM_001127500.3	c.*1428G>A		3_prime_UTR_variant	21/21
MET	NM_001324402.2	c.*1428G>A		3_prime_UTR_variant	20/20
MET	XM_011516223.2	c.*1428G>A		3_prime_UTR_variant	22/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MET	ENST00000397752.8	c.*1428G>A		3_prime_UTR_variant	21/21	1	NM_000245.4	P3
MET	ENST00000318493.11	c.*1428G>A		3_prime_UTR_variant	21/21	1		A2
MET	ENST00000436117.3	c.*3206G>A		3_prime_UTR_variant, NMD_transcript_variant	20/20	1

Frequencies

GnomAD3 genomes AF: 0.643 AC: 97703 AN: 151840 Hom.: 31864 Cov.: 31

Gnomad AFR AF: 0.543

Gnomad AMI AF: 0.669

Gnomad AMR AF: 0.674

Gnomad ASJ AF: 0.714

Gnomad EAS AF: 0.869

Gnomad SAS AF: 0.803

Gnomad FIN AF: 0.634

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.667

Gnomad OTH AF: 0.646

GnomAD4 exome AF: 0.692 AC: 52500 AN: 75828 Hom.: 18452 Cov.: 0 AF XY: 0.694 AC XY: 24279 AN XY: 35008

Gnomad4 AFR exome AF: 0.531

Gnomad4 AMR exome AF: 0.683

Gnomad4 ASJ exome AF: 0.708

Gnomad4 EAS exome AF: 0.865

Gnomad4 SAS exome AF: 0.827

Gnomad4 FIN exome AF: 0.628

Gnomad4 NFE exome AF: 0.667

Gnomad4 OTH exome AF: 0.667

GnomAD4 genome AF: 0.643 AC: 97763 AN: 151958 Hom.: 31873 Cov.: 31 AF XY: 0.646 AC XY: 47973 AN XY: 74266

Gnomad4 AFR AF: 0.543

Gnomad4 AMR AF: 0.673

Gnomad4 ASJ AF: 0.714

Gnomad4 EAS AF: 0.870

Gnomad4 SAS AF: 0.800

Gnomad4 FIN AF: 0.634

Gnomad4 NFE AF: 0.667

Gnomad4 OTH AF: 0.645

Alfa AF: 0.661 Hom.: 32070

Bravo AF: 0.640

Asia WGS AF: 0.820 AC: 2852 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Papillary renal cell carcinoma type 1 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Benign	0.76

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: rs1621; hg19: chr7-116437606;