7-116797450-A-G

Variant names:

• chr7-116797450-A-G
• rs41739
• ENST00000436117.3:n.*3104A>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.*3104A>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 0.38 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 ENST00000436117.3 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.301
• Publications: 14 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=-0.75).
• BP6: Variant 7-116797450-A-G is Benign according to our data. Variant chr7-116797450-A-G is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
MET	NM_000245.4	c.*1326A>G		3_prime_UTR_variant	Exon 21 of 21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.*1326A>G		3_prime_UTR_variant	Exon 21 of 21		NP_001120972.1
MET	NM_001324402.2	c.*1326A>G		3_prime_UTR_variant	Exon 20 of 20		NP_001311331.1
MET	XM_011516223.2	c.*1326A>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.*3104A>G		non_coding_transcript_exon_variant	Exon 20 of 20	1		ENSP00000410980.2
MET	ENST00000397752.8	c.*1326A>G		3_prime_UTR_variant	Exon 21 of 21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.*1326A>G		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*3104A>G		3_prime_UTR_variant	Exon 20 of 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

African (AFR) AF: 0.0973 AC: 350 AN: 3596

American (AMR) AF: 0.457 AC: 1046 AN: 2290

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 2344 AN: 4700

East Asian (EAS) AF: 0.506 AC: 5371 AN: 10608

South Asian (SAS) AF: 0.460 AC: 291 AN: 632

European-Finnish (FIN) AF: 0.404 AC: 194 AN: 480

Middle Eastern (MID) AF: 0.396 AC: 182 AN: 460

European-Non Finnish (NFE) AF: 0.451 AC: 20757 AN: 45998

Other (OTH) AF: 0.424 AC: 2642 AN: 6238

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

African (AFR) AF: 0.101 AC: 4169 AN: 41412

American (AMR) AF: 0.444 AC: 6768 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 1688 AN: 3468

East Asian (EAS) AF: 0.470 AC: 2416 AN: 5140

South Asian (SAS) AF: 0.456 AC: 2193 AN: 4804

European-Finnish (FIN) AF: 0.381 AC: 4018 AN: 10540

Middle Eastern (MID) AF: 0.408 AC: 119 AN: 292

European-Non Finnish (NFE) AF: 0.451 AC: 30631 AN: 67872

Other (OTH) AF: 0.387 AC: 814 AN: 2104

Alfa AF: 0.430 Hom.: 16629

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

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	-0.75
CADD	Benign	6.5
DANN	Benign	0.85
PhyloP100		-0.30
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: rs41739; hg19: chr7-116437504; COSMIC: COSV59272045; COSMIC: COSV59272045;