rs38845

Variant names:

• chr7-116681748-A-G
• rs38845
• NM_000245.4:c.-15+9171A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-116681748-A-G
• chr7-116681748-A-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+9171A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 152,012 control chromosomes in the GnomAD database, including 27,336 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 0.59 (27336 hom., cov: 31)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.224
• Publications: 17 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 = 0.741 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.-15+9171A>G		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+9171A>G		intron_variant	Intron 1 of 20	1	NM_000245.4	ENSP00000380860.3

Frequencies

GnomAD3 genomes AF: 0.591 AC: 89767 AN: 151894 Hom.: 27296 Cov.: 31

Gnomad AFR AF: 0.748

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.540

Gnomad ASJ AF: 0.518

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.642

Gnomad FIN AF: 0.546

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.559

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

GnomAD4 genome AF: 0.591 AC: 89855 AN: 152012 Hom.: 27336 Cov.: 31 AF XY: 0.593 AC XY: 44044 AN XY: 74312

African (AFR) AF: 0.748 AC: 31016 AN: 41458

American (AMR) AF: 0.539 AC: 8236 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 1800 AN: 3472

East Asian (EAS) AF: 0.555 AC: 2863 AN: 5162

South Asian (SAS) AF: 0.642 AC: 3093 AN: 4818

European-Finnish (FIN) AF: 0.546 AC: 5762 AN: 10562

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.521 AC: 35405 AN: 67954

Other (OTH) AF: 0.561 AC: 1183 AN: 2110

Alfa AF: 0.539 Hom.: 12370

Bravo AF: 0.595

Asia WGS AF: 0.593 AC: 2064 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	0.95
DANN	Benign	0.67
PhyloP100		-0.22
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: rs38845; hg19: chr7-116321802;