7-116699588-G-T

Variant names:

• chr7-116699588-G-T
• rs55985569
• NM_000245.4:c.504G>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000245.4(MET):​c.504G>T​(p.Glu168Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00651 in 1,613,976 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E168K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (40 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:20 O:1
• Conservation: PhyloP100: 1.05
• Publications: 46 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003328681).
• BP6: Variant 7-116699588-G-T is Benign according to our data. Variant chr7-116699588-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41627.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00407 (620/152278) while in subpopulation NFE AF = 0.00638 (434/68018). AF 95% confidence interval is 0.00588. There are 4 homozygotes in GnomAd4. There are 283 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR,Unknown gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	NM_000245.4	MANE Select	c.504G>T	p.Glu168Asp	missense	Exon 2 of 21	NP_000236.2
	MET	NM_001127500.3		c.504G>T	p.Glu168Asp	missense	Exon 2 of 21	NP_001120972.1	P08581-2
	MET	NM_001324401.3		c.504G>T	p.Glu168Asp	missense	Exon 2 of 12	NP_001311330.1	E6Y365

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	ENST00000397752.8	TSL:1 MANE Select	c.504G>T	p.Glu168Asp	missense	Exon 2 of 21	ENSP00000380860.3	P08581-1
	MET	ENST00000318493.11	TSL:1	c.504G>T	p.Glu168Asp	missense	Exon 2 of 21	ENSP00000317272.6	P08581-2
	MET	ENST00000456159.1	TSL:1	c.561G>T	p.Glu187Asp	missense	Exon 3 of 3	ENSP00000413857.1	C9JKM5

Frequencies

GnomAD3 genomes AF: 0.00407 AC: 620 AN: 152160 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00638

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00372 AC: 921 AN: 247338 AF XY: 0.00370

Gnomad AFR exome AF: 0.00176

Gnomad AMR exome AF: 0.00296

Gnomad ASJ exome AF: 0.00180

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000372

Gnomad NFE exome AF: 0.00666

Gnomad OTH exome AF: 0.00266

GnomAD4 exome AF: 0.00677 AC: 9892 AN: 1461698 Hom.: 40 Cov.: 32 AF XY: 0.00651 AC XY: 4731 AN XY: 727142

African (AFR) AF: 0.00149 AC: 50 AN: 33464

American (AMR) AF: 0.00327 AC: 146 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00199 AC: 52 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000359 AC: 31 AN: 86258

European-Finnish (FIN) AF: 0.000656 AC: 35 AN: 53360

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5764

European-Non Finnish (NFE) AF: 0.00827 AC: 9196 AN: 1111928

Other (OTH) AF: 0.00621 AC: 375 AN: 60384

GnomAD4 genome AF: 0.00407 AC: 620 AN: 152278 Hom.: 4 Cov.: 32 AF XY: 0.00380 AC XY: 283 AN XY: 74460

African (AFR) AF: 0.00152 AC: 63 AN: 41552

American (AMR) AF: 0.00503 AC: 77 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00638 AC: 434 AN: 68018

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

Alfa AF: 0.00548 Hom.: 2

Bravo AF: 0.00505

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.00201 AC: 8

ESP6500EA AF: 0.00686 AC: 57

ExAC AF: 0.00366 AC: 442

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00638

EpiControl AF: 0.00676

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	1	5	not specified (7)
-	-	4	Papillary renal cell carcinoma type 1 (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	1	Papillary renal cell carcinoma type 1;C2239176:Hepatocellular carcinoma;C4084709:Autosomal recessive nonsyndromic hearing loss 97;C4085248:Osteofibrous dysplasia;C5774205:Arthrogryposis, distal, IIa 11 (1)
-	-	1	Renal cell carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.081
Sift	Benign	0.11	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.94	P
Vest4		0.15
MutPred		0.33		Gain of relative solvent accessibility (P = 0.0249)
MVP		0.54
MPC		0.40
ClinPred		0.0039	T
GERP RS		4.9
Varity_R		0.25
gMVP		0.50
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55985569; hg19: chr7-116339642; COSMIC: COSV59258005;