chr7-116797152-A-G

Variant names:

• chr7-116797152-A-G
• rs41738
• ENST00000436117.3:n.*2806A>G

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.*2806A>G 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 0.371 in 200,028 control chromosomes in the GnomAD database, including 15,928 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (11164 hom., cov: 32)
  • Exomes 𝑓: 0.44 (4764 hom.)
• Consequence: MET ENST00000436117.3 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.25
• Publications: 10 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=-0.54).
• BP6: Variant 7-116797152-A-G is Benign according to our data. Variant chr7-116797152-A-G is described in ClinVar as Benign. ClinVar VariationId is 358713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.*1028A>G		3_prime_UTR_variant	Exon 21 of 21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.*1028A>G		3_prime_UTR_variant	Exon 21 of 21		NP_001120972.1
MET	NM_001324402.2	c.*1028A>G		3_prime_UTR_variant	Exon 20 of 20		NP_001311331.1
MET	XM_011516223.2	c.*1028A>G		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.*2806A>G		non_coding_transcript_exon_variant	Exon 20 of 20	1		ENSP00000410980.2
MET	ENST00000397752.8	c.*1028A>G		3_prime_UTR_variant	Exon 21 of 21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.*1028A>G		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*2806A>G		3_prime_UTR_variant	Exon 20 of 20	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53352 AN: 152042 Hom.: 11177 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.444

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.391

GnomAD4 exome AF: 0.438 AC: 20976 AN: 47868 Hom.: 4764 Cov.: 0 AF XY: 0.442 AC XY: 9791 AN XY: 22160

African (AFR) AF: 0.0984 AC: 210 AN: 2134

American (AMR) AF: 0.470 AC: 628 AN: 1336

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 1502 AN: 3028

East Asian (EAS) AF: 0.501 AC: 3818 AN: 7628

South Asian (SAS) AF: 0.454 AC: 189 AN: 416

European-Finnish (FIN) AF: 0.433 AC: 39 AN: 90

Middle Eastern (MID) AF: 0.372 AC: 111 AN: 298

European-Non Finnish (NFE) AF: 0.444 AC: 12847 AN: 28924

Other (OTH) AF: 0.407 AC: 1632 AN: 4014

GnomAD4 genome AF: 0.350 AC: 53326 AN: 152160 Hom.: 11164 Cov.: 32 AF XY: 0.353 AC XY: 26232 AN XY: 74390

African (AFR) AF: 0.103 AC: 4281 AN: 41550

American (AMR) AF: 0.444 AC: 6789 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 1691 AN: 3472

East Asian (EAS) AF: 0.471 AC: 2441 AN: 5178

South Asian (SAS) AF: 0.457 AC: 2202 AN: 4822

European-Finnish (FIN) AF: 0.381 AC: 4032 AN: 10576

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.451 AC: 30673 AN: 67966

Other (OTH) AF: 0.386 AC: 816 AN: 2112

Alfa AF: 0.425 Hom.: 16965

Bravo AF: 0.346

Asia WGS AF: 0.415 AC: 1440 AN: 3476

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	-0.54
CADD	Benign	6.8
DANN	Benign	0.80
PhyloP100		1.3
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: rs41738; hg19: chr7-116437206;