NM_000245.4:c.1201-13678A>G

Variant names:

• chr7-116717990-A-G
• rs38855
• NM_000245.4:c.1201-13678A>G

Variant summary

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

The NM_000245.4(MET):​c.1201-13678A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 152,092 control chromosomes in the GnomAD database, including 13,920 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 (13920 hom., cov: 32)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.344
• Publications: 59 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000245.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	NM_000245.4	MANE Select	c.1201-13678A>G		intron	N/A	NP_000236.2
	MET	NM_001127500.3		c.1201-13678A>G		intron	N/A	NP_001120972.1
	MET	NM_001324402.2		c.-90-13678A>G		intron	N/A	NP_001311331.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	ENST00000397752.8	TSL:1 MANE Select	c.1201-13678A>G		intron	N/A	ENSP00000380860.3
	MET	ENST00000318493.11	TSL:1	c.1201-13678A>G		intron	N/A	ENSP00000317272.6
	MET	ENST00000436117.3	TSL:1	n.1201-13678A>G		intron	N/A	ENSP00000410980.2

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61950 AN: 151974 Hom.: 13926 Cov.: 32

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.468

Gnomad EAS AF: 0.583

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.448

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.431

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

GnomAD4 genome AF: 0.407 AC: 61967 AN: 152092 Hom.: 13920 Cov.: 32 AF XY: 0.414 AC XY: 30796 AN XY: 74340

African (AFR) AF: 0.202 AC: 8380 AN: 41516

American (AMR) AF: 0.534 AC: 8155 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.468 AC: 1622 AN: 3466

East Asian (EAS) AF: 0.584 AC: 3027 AN: 5186

South Asian (SAS) AF: 0.533 AC: 2561 AN: 4808

European-Finnish (FIN) AF: 0.448 AC: 4729 AN: 10552

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

European-Non Finnish (NFE) AF: 0.473 AC: 32189 AN: 67984

Other (OTH) AF: 0.430 AC: 909 AN: 2114

Alfa AF: 0.455 Hom.: 71200

Bravo AF: 0.403

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.51
DANN	Benign	0.61
PhyloP100		-0.34
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: rs38855; hg19: chr7-116358044;