rs41739

Positions:

• chr7-116797450-A-G
• chr7-116797450-A-T

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.*1326A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 226,770 control chromosomes in the GnomAD database, including 18,769 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (11119 hom., cov: 30)
  • Exomes 𝑓: 0.44 (7650 hom.)
• Consequence: MET NM_000245.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.301

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=-0.75).
• BP6: Variant 7-116797450-A-G is Benign according to our data. Variant chr7-116797450-A-G is described in ClinVar as [Benign]. Clinvar id is 358716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.*1326A>G		3_prime_UTR_variant	21/21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.*1326A>G		3_prime_UTR_variant	21/21		NP_001120972.1
MET	NM_001324402.2	c.*1326A>G		3_prime_UTR_variant	20/20		NP_001311331.1
MET	XM_011516223.2	c.*1326A>G		3_prime_UTR_variant	22/22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.*1326A>G		3_prime_UTR_variant	21/21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.*1326A>G		3_prime_UTR_variant	21/21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*3104A>G		non_coding_transcript_exon_variant	20/20	1		ENSP00000410980.2
MET	ENST00000436117.3	n.*3104A>G		3_prime_UTR_variant	20/20	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes AF: 0.350 AC: 53117 AN: 151650 Hom.: 11132 Cov.: 30

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.444

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.392

GnomAD4 exome AF: 0.442 AC: 33177 AN: 75002 Hom.: 7650 Cov.: 0 AF XY: 0.447 AC XY: 15479 AN XY: 34646

Gnomad4 AFR exome AF: 0.0973

Gnomad4 AMR exome AF: 0.457

Gnomad4 ASJ exome AF: 0.499

Gnomad4 EAS exome AF: 0.506

Gnomad4 SAS exome AF: 0.460

Gnomad4 FIN exome AF: 0.404

Gnomad4 NFE exome AF: 0.451

Gnomad4 OTH exome AF: 0.424

GnomAD4 genome AF: 0.350 AC: 53093 AN: 151768 Hom.: 11119 Cov.: 30 AF XY: 0.352 AC XY: 26104 AN XY: 74150

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.444

Gnomad4 ASJ AF: 0.487

Gnomad4 EAS AF: 0.470

Gnomad4 SAS AF: 0.456

Gnomad4 FIN AF: 0.381

Gnomad4 NFE AF: 0.451

Gnomad4 OTH AF: 0.387

Alfa AF: 0.433 Hom.: 14121

Bravo AF: 0.345

Asia WGS AF: 0.414 AC: 1439 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	-0.75
CADD	Benign	6.5
DANN	Benign	0.85

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: rs41739; hg19: chr7-116437504; COSMIC: COSV59272045; COSMIC: COSV59272045;