7-116701329-A-G

Variant names:

• chr7-116701329-A-G
• rs2299436
• NM_000245.4:c.1200+1045A>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.1200+1045A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 152,038 control chromosomes in the GnomAD database, including 4,525 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 0.24 (4525 hom., cov: 32)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.17
• Publications: 6 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.329 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.1200+1045A>G		intron	N/A	NP_000236.2
	MET	NM_001127500.3		c.1200+1045A>G		intron	N/A	NP_001120972.1
	MET	NM_001324402.2		c.-91+28752A>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.1200+1045A>G		intron	N/A	ENSP00000380860.3
	MET	ENST00000318493.11	TSL:1	c.1200+1045A>G		intron	N/A	ENSP00000317272.6
	MET	ENST00000436117.3	TSL:1	n.1200+1045A>G		intron	N/A	ENSP00000410980.2

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36638 AN: 151920 Hom.: 4509 Cov.: 32

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.342

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.229

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

GnomAD4 genome AF: 0.241 AC: 36695 AN: 152038 Hom.: 4525 Cov.: 32 AF XY: 0.240 AC XY: 17852 AN XY: 74330

African (AFR) AF: 0.208 AC: 8642 AN: 41472

American (AMR) AF: 0.229 AC: 3496 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 850 AN: 3468

East Asian (EAS) AF: 0.343 AC: 1772 AN: 5170

South Asian (SAS) AF: 0.259 AC: 1249 AN: 4822

European-Finnish (FIN) AF: 0.238 AC: 2512 AN: 10576

Middle Eastern (MID) AF: 0.243 AC: 71 AN: 292

European-Non Finnish (NFE) AF: 0.254 AC: 17259 AN: 67954

Other (OTH) AF: 0.233 AC: 493 AN: 2114

Alfa AF: 0.252 Hom.: 3245

Bravo AF: 0.239

Asia WGS AF: 0.322 AC: 1116 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.095
DANN	Benign	0.48
PhyloP100		-1.2
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: rs2299436; hg19: chr7-116341383;