7-116684477-C-T

Variant names:

• chr7-116684477-C-T
• rs38846
• NM_000245.4:c.-15+11900C>T

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+11900C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.82 in 152,182 control chromosomes in the GnomAD database, including 51,373 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 0.82 (51373 hom., cov: 32)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.52
• Publications: 8 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 = 0.946 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	NM_000245.4	MANE Select	c.-15+11900C>T		intron	N/A	NP_000236.2
	MET	NM_001127500.3		c.-15+11900C>T		intron	N/A	NP_001120972.1	P08581-2
	MET	NM_001324402.2		c.-91+11900C>T		intron	N/A	NP_001311331.1	B4DLF5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	ENST00000397752.8	TSL:1 MANE Select	c.-15+11900C>T		intron	N/A	ENSP00000380860.3	P08581-1
	MET	ENST00000318493.11	TSL:1	c.-15+11900C>T		intron	N/A	ENSP00000317272.6	P08581-2
	MET	ENST00000456159.1	TSL:1	c.-7-11273C>T		intron	N/A	ENSP00000413857.1	C9JKM5

Frequencies

GnomAD3 genomes AF: 0.820 AC: 124734 AN: 152064 Hom.: 51319 Cov.: 32

Gnomad AFR AF: 0.828

Gnomad AMI AF: 0.771

Gnomad AMR AF: 0.805

Gnomad ASJ AF: 0.805

Gnomad EAS AF: 0.969

Gnomad SAS AF: 0.912

Gnomad FIN AF: 0.813

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.805

Gnomad OTH AF: 0.791

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

GnomAD4 genome AF: 0.820 AC: 124842 AN: 152182 Hom.: 51373 Cov.: 32 AF XY: 0.823 AC XY: 61247 AN XY: 74410

African (AFR) AF: 0.828 AC: 34377 AN: 41508

American (AMR) AF: 0.805 AC: 12299 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.805 AC: 2796 AN: 3472

East Asian (EAS) AF: 0.969 AC: 5024 AN: 5186

South Asian (SAS) AF: 0.912 AC: 4401 AN: 4828

European-Finnish (FIN) AF: 0.813 AC: 8595 AN: 10578

Middle Eastern (MID) AF: 0.827 AC: 243 AN: 294

European-Non Finnish (NFE) AF: 0.805 AC: 54735 AN: 68010

Other (OTH) AF: 0.792 AC: 1669 AN: 2108

Alfa AF: 0.813 Hom.: 85406

Bravo AF: 0.818

Asia WGS AF: 0.919 AC: 3195 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	0.28
DANN	Benign	0.20
PhyloP100		-1.5
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: rs38846; hg19: chr7-116324531;