7-116697298-T-G

Variant names:

• chr7-116697298-T-G
• rs2237710
• NM_000245.4:c.-14-1773T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000245.4(MET):​c.-14-1773T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 151,910 control chromosomes in the GnomAD database, including 7,561 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (7561 hom., cov: 32)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.335
• Publications: 7 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]

COMETT (HGNC:51196): (cytosolic oncogenic antisense to MET transcript) This gene encodes a natural antisense transcript highly expressed in papillary thyroid carcinomas harboring BRAF V600E mutation or RET gene rearrangements. This lncRNA induces the downstream MAPK pathway and is part of a co-expression network including different oncogenes belonging to the MAPK and PI3H/AKT pathways. In thyroid carcinomas, this gene has oncogenic properties associated with increased proliferation and drug resistance. [provided by RefSeq, Jan 2020]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000245.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	NM_000245.4	MANE Select	c.-14-1773T>G		intron	N/A	NP_000236.2
	MET	NM_001127500.3		c.-14-1773T>G		intron	N/A	NP_001120972.1
	MET	NM_001324402.2		c.-91+24721T>G		intron	N/A	NP_001311331.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	ENST00000397752.8	TSL:1 MANE Select	c.-14-1773T>G		intron	N/A	ENSP00000380860.3
	MET	ENST00000318493.11	TSL:1	c.-14-1773T>G		intron	N/A	ENSP00000317272.6
	MET	ENST00000456159.1	TSL:1	c.43+1499T>G		intron	N/A	ENSP00000413857.1

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47547 AN: 151792 Hom.: 7529 Cov.: 32

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.441

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.303

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.314 AC: 47628 AN: 151910 Hom.: 7561 Cov.: 32 AF XY: 0.312 AC XY: 23134 AN XY: 74232

African (AFR) AF: 0.348 AC: 14425 AN: 41438

American (AMR) AF: 0.272 AC: 4147 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 967 AN: 3468

East Asian (EAS) AF: 0.405 AC: 2090 AN: 5166

South Asian (SAS) AF: 0.369 AC: 1771 AN: 4796

European-Finnish (FIN) AF: 0.290 AC: 3054 AN: 10530

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20037 AN: 67948

Other (OTH) AF: 0.307 AC: 647 AN: 2106

Alfa AF: 0.302 Hom.: 3946

Bravo AF: 0.312

Asia WGS AF: 0.422 AC: 1463 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.41
PhyloP100		-0.34
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: rs2237710; hg19: chr7-116337352;