7-116701434-G-A

Variant names:

• chr7-116701434-G-A
• rs2299437
• NM_000245.4:c.1200+1150G>A

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+1150G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 151,996 control chromosomes in the GnomAD database, including 4,532 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 (4532 hom., cov: 32)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.672
• 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=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.328 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+1150G>A		intron	N/A	NP_000236.2
	MET	NM_001127500.3		c.1200+1150G>A		intron	N/A	NP_001120972.1
	MET	NM_001324402.2		c.-91+28857G>A		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+1150G>A		intron	N/A	ENSP00000380860.3
	MET	ENST00000318493.11	TSL:1	c.1200+1150G>A		intron	N/A	ENSP00000317272.6
	MET	ENST00000436117.3	TSL:1	n.1200+1150G>A		intron	N/A	ENSP00000410980.2

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36658 AN: 151876 Hom.: 4516 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.231

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: 0.242 AC: 36716 AN: 151996 Hom.: 4532 Cov.: 32 AF XY: 0.240 AC XY: 17848 AN XY: 74298

African (AFR) AF: 0.210 AC: 8696 AN: 41484

American (AMR) AF: 0.229 AC: 3498 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 850 AN: 3464

East Asian (EAS) AF: 0.341 AC: 1761 AN: 5166

South Asian (SAS) AF: 0.259 AC: 1245 AN: 4802

European-Finnish (FIN) AF: 0.238 AC: 2516 AN: 10574

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.254 AC: 17237 AN: 67934

Other (OTH) AF: 0.233 AC: 491 AN: 2108

Alfa AF: 0.252 Hom.: 3243

Bravo AF: 0.239

Asia WGS AF: 0.321 AC: 1115 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	9.5
DANN	Benign	0.50
PhyloP100		0.67
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: rs2299437; hg19: chr7-116341488;