NM_000245.4:c.-15+355T>C

Variant names:

• chr7-116672932-T-C
• rs38840
• NM_000245.4:c.-15+355T>C

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+355T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.862 in 152,092 control chromosomes in the GnomAD database, including 56,675 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 0.86 (56675 hom., cov: 30)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.48
• Publications: 7 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.908 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.-15+355T>C		intron_variant	Intron 1 of 20	ENST00000397752.8	NP_000236.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.-15+355T>C		intron_variant	Intron 1 of 20	1	NM_000245.4	ENSP00000380860.3

Frequencies

GnomAD3 genomes AF: 0.862 AC: 131072 AN: 151974 Hom.: 56628 Cov.: 30

Gnomad AFR AF: 0.916

Gnomad AMI AF: 0.831

Gnomad AMR AF: 0.854

Gnomad ASJ AF: 0.887

Gnomad EAS AF: 0.892

Gnomad SAS AF: 0.844

Gnomad FIN AF: 0.857

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.831

Gnomad OTH AF: 0.859

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

GnomAD4 genome AF: 0.862 AC: 131177 AN: 152092 Hom.: 56675 Cov.: 30 AF XY: 0.866 AC XY: 64334 AN XY: 74320

African (AFR) AF: 0.916 AC: 38006 AN: 41502

American (AMR) AF: 0.855 AC: 13064 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.887 AC: 3078 AN: 3472

East Asian (EAS) AF: 0.892 AC: 4603 AN: 5158

South Asian (SAS) AF: 0.843 AC: 4046 AN: 4798

European-Finnish (FIN) AF: 0.857 AC: 9067 AN: 10578

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.831 AC: 56490 AN: 67986

Other (OTH) AF: 0.857 AC: 1808 AN: 2110

Alfa AF: 0.839 Hom.: 27366

Bravo AF: 0.866

Asia WGS AF: 0.850 AC: 2956 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.6
DANN	Benign	0.52
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: rs38840; hg19: chr7-116312986;