chr7-116714471-T-A

Variant names:

• chr7-116714471-T-A
• rs38852
• NM_000245.4:c.1200+14187T>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.1200+14187T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 151,994 control chromosomes in the GnomAD database, including 13,917 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 0.41 (13917 hom., cov: 31)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25
• Publications: 3 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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.1200+14187T>A		intron_variant	Intron 2 of 20	ENST00000397752.8	NP_000236.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.1200+14187T>A		intron_variant	Intron 2 of 20	1	NM_000245.4	ENSP00000380860.3

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61946 AN: 151876 Hom.: 13923 Cov.: 31

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.535

Gnomad ASJ AF: 0.468

Gnomad EAS AF: 0.586

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.431

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

GnomAD4 genome AF: 0.408 AC: 61963 AN: 151994 Hom.: 13917 Cov.: 31 AF XY: 0.415 AC XY: 30802 AN XY: 74302

African (AFR) AF: 0.202 AC: 8382 AN: 41472

American (AMR) AF: 0.535 AC: 8168 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.468 AC: 1624 AN: 3468

East Asian (EAS) AF: 0.586 AC: 3028 AN: 5164

South Asian (SAS) AF: 0.532 AC: 2564 AN: 4816

European-Finnish (FIN) AF: 0.449 AC: 4728 AN: 10540

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.473 AC: 32166 AN: 67942

Other (OTH) AF: 0.430 AC: 908 AN: 2110

Alfa AF: 0.433 Hom.: 1880

Bravo AF: 0.403

Asia WGS AF: 0.536 AC: 1864 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.75
DANN	Benign	0.76
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: rs38852; hg19: chr7-116354525;