7-116678948-A-G

Variant names:

• chr7-116678948-A-G
• rs714180
• NM_000245.4:c.-15+6371A>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.-15+6371A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.603 in 151,964 control chromosomes in the GnomAD database, including 29,459 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 0.60 (29459 hom., cov: 31)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.569
• Publications: 12 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=-0.77).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.823 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.-15+6371A>G		intron	N/A	NP_000236.2
	MET	NM_001127500.3		c.-15+6371A>G		intron	N/A	NP_001120972.1
	MET	NM_001324402.2		c.-91+6371A>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.-15+6371A>G		intron	N/A	ENSP00000380860.3
	MET	ENST00000318493.11	TSL:1	c.-15+6371A>G		intron	N/A	ENSP00000317272.6
	MET	ENST00000456159.1	TSL:1	c.-8+6371A>G		intron	N/A	ENSP00000413857.1

Frequencies

GnomAD3 genomes AF: 0.602 AC: 91486 AN: 151846 Hom.: 29401 Cov.: 31

Gnomad AFR AF: 0.830

Gnomad AMI AF: 0.631

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.579

Gnomad SAS AF: 0.626

Gnomad FIN AF: 0.597

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.580

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

GnomAD4 genome AF: 0.603 AC: 91599 AN: 151964 Hom.: 29459 Cov.: 31 AF XY: 0.603 AC XY: 44783 AN XY: 74292

African (AFR) AF: 0.830 AC: 34405 AN: 41458

American (AMR) AF: 0.427 AC: 6520 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 1698 AN: 3468

East Asian (EAS) AF: 0.579 AC: 2997 AN: 5172

South Asian (SAS) AF: 0.626 AC: 3018 AN: 4822

European-Finnish (FIN) AF: 0.597 AC: 6287 AN: 10534

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.511 AC: 34704 AN: 67934

Other (OTH) AF: 0.582 AC: 1230 AN: 2112

Alfa AF: 0.538 Hom.: 95825

Bravo AF: 0.599

Asia WGS AF: 0.585 AC: 2036 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.65
PhyloP100		0.57
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: rs714180; hg19: chr7-116319002;