rs80153920

Variant names:

• chr7-116695757-A-T
• rs80153920
• ENST00000456159.1:c.1A>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.-14-3314A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0477 in 490,252 control chromosomes in the GnomAD database, including 761 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.059 (341 hom., cov: 32)
  • Exomes 𝑓: 0.043 (420 hom.)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.325
• Publications: 12 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 (MetaRNN=0.0027790964).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0937 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.-14-3314A>T		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.-14-3314A>T		intron_variant	Intron 1 of 20	1	NM_000245.4	ENSP00000380860.3

Frequencies

GnomAD3 genomes AF: 0.0586 AC: 8911 AN: 152164 Hom.: 335 Cov.: 32

Gnomad AFR AF: 0.0959

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0796

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.0695

Gnomad SAS AF: 0.0447

Gnomad FIN AF: 0.00932

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0409

Gnomad OTH AF: 0.0511

GnomAD2 exomes AF: 0.0475 AC: 6981 AN: 147110 AF XY: 0.0460

Gnomad AFR exome AF: 0.0990

Gnomad AMR exome AF: 0.0755

Gnomad ASJ exome AF: 0.0248

Gnomad EAS exome AF: 0.0672

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.0432

Gnomad OTH exome AF: 0.0453

GnomAD4 exome AF: 0.0428 AC: 14458 AN: 337970 Hom.: 420 Cov.: 0 AF XY: 0.0426 AC XY: 8029 AN XY: 188650

African (AFR) AF: 0.101 AC: 927 AN: 9206

American (AMR) AF: 0.0757 AC: 2078 AN: 27462

Ashkenazi Jewish (ASJ) AF: 0.0244 AC: 296 AN: 12148

East Asian (EAS) AF: 0.0666 AC: 944 AN: 14170

South Asian (SAS) AF: 0.0393 AC: 2324 AN: 59198

European-Finnish (FIN) AF: 0.0105 AC: 278 AN: 26588

Middle Eastern (MID) AF: 0.0512 AC: 149 AN: 2910

European-Non Finnish (NFE) AF: 0.0396 AC: 6749 AN: 170266

Other (OTH) AF: 0.0445 AC: 713 AN: 16022

GnomAD4 genome AF: 0.0587 AC: 8944 AN: 152282 Hom.: 341 Cov.: 32 AF XY: 0.0581 AC XY: 4323 AN XY: 74456

African (AFR) AF: 0.0962 AC: 3997 AN: 41544

American (AMR) AF: 0.0794 AC: 1215 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3470

East Asian (EAS) AF: 0.0697 AC: 361 AN: 5180

South Asian (SAS) AF: 0.0450 AC: 217 AN: 4824

European-Finnish (FIN) AF: 0.00932 AC: 99 AN: 10624

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0409 AC: 2783 AN: 68020

Other (OTH) AF: 0.0549 AC: 116 AN: 2114

Alfa AF: 0.0461 Hom.: 65

Bravo AF: 0.0647

TwinsUK AF: 0.0472 AC: 175

ALSPAC AF: 0.0446 AC: 172

ExAC AF: 0.0354 AC: 687

Asia WGS AF: 0.0710 AC: 247 AN: 3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	7.6
DANN	Benign	0.34
Eigen	Benign	-0.88
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.034	N
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.97	T
PhyloP100		-0.33
PROVEAN	Benign	0.0	N
REVEL	Benign	0.017
Sift	Pathogenic	0.0	D
MutPred		0.87		Loss of MoRF binding (P = 0.148);
ClinPred		0.0018	T
GERP RS		-2.0
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: rs80153920; hg19: chr7-116335811; COSMIC: COSV59261148; COSMIC: COSV59261148;