rs38850

Variant names:

• chr7-116697595-G-A
• rs38850
• NM_000245.4:c.-14-1476G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000245.4(MET):​c.-14-1476G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 152,024 control chromosomes in the GnomAD database, including 3,956 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 0.20 (3956 hom., cov: 32)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.-14-1476G>A		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.-14-1476G>A		intron_variant	Intron 1 of 20	1	NM_000245.4	ENSP00000380860.3

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30239 AN: 151906 Hom.: 3959 Cov.: 32

Gnomad AFR AF: 0.0531

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.236

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

GnomAD4 genome AF: 0.199 AC: 30222 AN: 152024 Hom.: 3956 Cov.: 32 AF XY: 0.193 AC XY: 14364 AN XY: 74294

African (AFR) AF: 0.0529 AC: 2197 AN: 41492

American (AMR) AF: 0.192 AC: 2926 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 856 AN: 3470

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5182

South Asian (SAS) AF: 0.115 AC: 556 AN: 4824

European-Finnish (FIN) AF: 0.234 AC: 2466 AN: 10524

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.301 AC: 20467 AN: 67950

Other (OTH) AF: 0.233 AC: 491 AN: 2106

Alfa AF: 0.261 Hom.: 7702

Bravo AF: 0.188

Asia WGS AF: 0.0520 AC: 181 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	8.3
DANN	Benign	0.64
PhyloP100		1.2
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: rs38850; hg19: chr7-116337649;