chr7-116797552-G-A

Variant names:

• chr7-116797552-G-A
• rs1621
• ENST00000436117.3:n.*3206G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000436117.3(MET):​n.*3206G>A variant causes a non coding transcript exon 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 ENST00000436117.3 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.54
• Publications: 33 publications found

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]

MET Gene-Disease associations (from GenCC):

• hereditary papillary renal cell carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• papillary renal cell carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen
• autosomal recessive nonsyndromic hearing loss 97

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• osteofibrous dysplasia

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• arthrogryposis, distal, IIa 11

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
MET	NM_000245.4	c.*1428G>A		3_prime_UTR_variant	Exon 21 of 21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.*1428G>A		3_prime_UTR_variant	Exon 21 of 21		NP_001120972.1
MET	NM_001324402.2	c.*1428G>A		3_prime_UTR_variant	Exon 20 of 20		NP_001311331.1
MET	XM_011516223.2	c.*1428G>A		3_prime_UTR_variant	Exon 22 of 22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000436117.3	n.*3206G>A		non_coding_transcript_exon_variant	Exon 20 of 20	1		ENSP00000410980.2
MET	ENST00000397752.8	c.*1428G>A		3_prime_UTR_variant	Exon 21 of 21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.*1428G>A		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*3206G>A		3_prime_UTR_variant	Exon 20 of 20	1		ENSP00000410980.2

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

African (AFR) AF: 0.531 AC: 1892 AN: 3562

American (AMR) AF: 0.683 AC: 1576 AN: 2308

Ashkenazi Jewish (ASJ) AF: 0.708 AC: 3372 AN: 4762

East Asian (EAS) AF: 0.865 AC: 9182 AN: 10618

South Asian (SAS) AF: 0.827 AC: 539 AN: 652

European-Finnish (FIN) AF: 0.628 AC: 304 AN: 484

Middle Eastern (MID) AF: 0.621 AC: 288 AN: 464

European-Non Finnish (NFE) AF: 0.667 AC: 31125 AN: 46650

Other (OTH) AF: 0.667 AC: 4222 AN: 6328

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

African (AFR) AF: 0.543 AC: 22499 AN: 41414

American (AMR) AF: 0.673 AC: 10287 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.714 AC: 2476 AN: 3470

East Asian (EAS) AF: 0.870 AC: 4501 AN: 5176

South Asian (SAS) AF: 0.800 AC: 3852 AN: 4812

European-Finnish (FIN) AF: 0.634 AC: 6686 AN: 10552

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.667 AC: 45307 AN: 67940

Other (OTH) AF: 0.645 AC: 1363 AN: 2112

Alfa AF: 0.655 Hom.: 41638

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

Papillary renal cell carcinoma type 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Benign	0.76
PhyloP100		2.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1621; hg19: chr7-116437606;