NM_000245.4:c.-14-11695C>G

Variant names:

• chr7-116687376-C-G
• rs39748
• NM_000245.4:c.-14-11695C>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.-14-11695C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 152,140 control chromosomes in the GnomAD database, including 10,939 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 0.35 (10939 hom., cov: 32)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.284
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.45 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.-14-11695C>G		intron	N/A	NP_000236.2
	MET	NM_001127500.3		c.-14-11695C>G		intron	N/A	NP_001120972.1
	MET	NM_001324402.2		c.-91+14799C>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.-14-11695C>G		intron	N/A	ENSP00000380860.3
	MET	ENST00000318493.11	TSL:1	c.-14-11695C>G		intron	N/A	ENSP00000317272.6
	MET	ENST00000456159.1	TSL:1	c.-7-8374C>G		intron	N/A	ENSP00000413857.1

Frequencies

GnomAD3 genomes AF: 0.346 AC: 52635 AN: 152022 Hom.: 10944 Cov.: 32

Gnomad AFR AF: 0.0959

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.442

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.376

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

GnomAD4 genome AF: 0.346 AC: 52621 AN: 152140 Hom.: 10939 Cov.: 32 AF XY: 0.350 AC XY: 26043 AN XY: 74350

African (AFR) AF: 0.0956 AC: 3970 AN: 41536

American (AMR) AF: 0.459 AC: 7021 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 1561 AN: 3472

East Asian (EAS) AF: 0.453 AC: 2342 AN: 5172

South Asian (SAS) AF: 0.442 AC: 2131 AN: 4822

European-Finnish (FIN) AF: 0.390 AC: 4117 AN: 10558

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.446 AC: 30334 AN: 67974

Other (OTH) AF: 0.371 AC: 784 AN: 2112

Alfa AF: 0.378 Hom.: 1495

Bravo AF: 0.340

Asia WGS AF: 0.395 AC: 1374 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.5
DANN	Benign	0.62
PhyloP100		0.28
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: rs39748; hg19: chr7-116327430;