rs40238

Variant names:

• chr7-116674273-A-C
• rs40238
• NM_000245.4:c.-15+1696A>C

Your query was ambiguous. Multiple possible variants found:

• chr7-116674273-A-C
• chr7-116674273-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+1696A>C 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 152,080 control chromosomes in the GnomAD database, including 51,140 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 (51140 hom., cov: 32)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.665
• 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.-15+1696A>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+1696A>C		intron_variant	Intron 1 of 20	1	NM_000245.4	ENSP00000380860.3

Frequencies

GnomAD3 genomes AF: 0.820 AC: 124567 AN: 151962 Hom.: 51115 Cov.: 32

Gnomad AFR AF: 0.836

Gnomad AMI AF: 0.796

Gnomad AMR AF: 0.833

Gnomad ASJ AF: 0.880

Gnomad EAS AF: 0.889

Gnomad SAS AF: 0.838

Gnomad FIN AF: 0.806

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.799

Gnomad OTH AF: 0.830

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

GnomAD4 genome AF: 0.820 AC: 124640 AN: 152080 Hom.: 51140 Cov.: 32 AF XY: 0.823 AC XY: 61213 AN XY: 74336

African (AFR) AF: 0.836 AC: 34644 AN: 41442

American (AMR) AF: 0.833 AC: 12746 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.880 AC: 3054 AN: 3472

East Asian (EAS) AF: 0.889 AC: 4607 AN: 5180

South Asian (SAS) AF: 0.837 AC: 4039 AN: 4828

European-Finnish (FIN) AF: 0.806 AC: 8511 AN: 10562

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.799 AC: 54313 AN: 67980

Other (OTH) AF: 0.828 AC: 1751 AN: 2114

Alfa AF: 0.793 Hom.: 7103

Bravo AF: 0.825

Asia WGS AF: 0.837 AC: 2901 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.4
DANN	Benign	0.75
PhyloP100		-0.67
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: rs40238; hg19: chr7-116314327;