7-116689929-C-T

Variant names:

• chr7-116689929-C-T
• rs12539654
• NM_000245.4:c.-14-9142C>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.-14-9142C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0614 in 152,024 control chromosomes in the GnomAD database, including 392 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 0.061 (392 hom., cov: 31)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.508
• Publications: 4 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 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.-14-9142C>T		intron	N/A	NP_000236.2
	MET	NM_001127500.3		c.-14-9142C>T		intron	N/A	NP_001120972.1	P08581-2
	MET	NM_001324402.2		c.-91+17352C>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.-14-9142C>T		intron	N/A	ENSP00000380860.3	P08581-1
	MET	ENST00000318493.11	TSL:1	c.-14-9142C>T		intron	N/A	ENSP00000317272.6	P08581-2
	MET	ENST00000456159.1	TSL:1	c.-7-5821C>T		intron	N/A	ENSP00000413857.1	C9JKM5

Frequencies

GnomAD3 genomes AF: 0.0612 AC: 9294 AN: 151906 Hom.: 383 Cov.: 31

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0806

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.0700

Gnomad SAS AF: 0.0439

Gnomad FIN AF: 0.00945

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0409

Gnomad OTH AF: 0.0513

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

GnomAD4 genome AF: 0.0614 AC: 9335 AN: 152024 Hom.: 392 Cov.: 31 AF XY: 0.0604 AC XY: 4488 AN XY: 74316

African (AFR) AF: 0.106 AC: 4379 AN: 41442

American (AMR) AF: 0.0804 AC: 1228 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 87 AN: 3468

East Asian (EAS) AF: 0.0701 AC: 363 AN: 5176

South Asian (SAS) AF: 0.0442 AC: 212 AN: 4798

European-Finnish (FIN) AF: 0.00945 AC: 100 AN: 10578

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0409 AC: 2780 AN: 67980

Other (OTH) AF: 0.0550 AC: 116 AN: 2108

Alfa AF: 0.0486 Hom.: 31

Bravo AF: 0.0676

Asia WGS AF: 0.0680 AC: 237 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.4
DANN	Benign	0.51
PhyloP100		-0.51
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: rs12539654; hg19: chr7-116329983;