7-116695774-G-C

Variant names:

• chr7-116695774-G-C
• rs80048442
• ENST00000456159.1:c.18G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000245.4(MET):​c.-14-3297G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 491,904 control chromosomes in the GnomAD database, including 2 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 0.0033 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.943
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037544668).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00332 (505/152292) while in subpopulation AFR AF = 0.011 (459/41552). AF 95% confidence interval is 0.0102. There are 2 homozygotes in GnomAd4. There are 240 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.-14-3297G>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.-14-3297G>C		intron_variant	Intron 1 of 20	1	NM_000245.4	ENSP00000380860.3

Frequencies

GnomAD3 genomes AF: 0.00331 AC: 504 AN: 152174 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000542 AC: 80 AN: 147618 AF XY: 0.000540

Gnomad AFR exome AF: 0.00865

Gnomad AMR exome AF: 0.000658

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.000940

GnomAD4 exome AF: 0.000333 AC: 113 AN: 339612 Hom.: 0 Cov.: 0 AF XY: 0.000280 AC XY: 53 AN XY: 189500

African (AFR) AF: 0.00831 AC: 77 AN: 9270

American (AMR) AF: 0.000688 AC: 19 AN: 27612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12202

East Asian (EAS) AF: 0.00 AC: 0 AN: 14308

South Asian (SAS) AF: 0.00 AC: 0 AN: 59428

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26694

Middle Eastern (MID) AF: 0.000687 AC: 2 AN: 2912

European-Non Finnish (NFE) AF: 0.0000234 AC: 4 AN: 171050

Other (OTH) AF: 0.000682 AC: 11 AN: 16136

GnomAD4 genome AF: 0.00332 AC: 505 AN: 152292 Hom.: 2 Cov.: 32 AF XY: 0.00322 AC XY: 240 AN XY: 74474

African (AFR) AF: 0.0110 AC: 459 AN: 41552

American (AMR) AF: 0.00242 AC: 37 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000157 Hom.: 0

Bravo AF: 0.00369

ExAC AF: 0.000511 AC: 10

Asia WGS AF: 0.000866 AC: 3 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	-0.69
CADD	Benign	7.6
DANN	Benign	0.62
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.94
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.033
Sift	Pathogenic	0.0	D
MutPred		0.18		Gain of ubiquitination at K4 (P = 0.0121);
MVP		0.10
ClinPred		0.030	T
GERP RS		2.3
Mutation Taster		=100/0	polymorphism

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: rs80048442; hg19: chr7-116335828; COSMIC: COSV104626976;