rs764960693

chr7-116763078-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000245.4(MET):c.2393T>G(p.Ile798Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I798L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.83

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MET	NM_000245.4	c.2393T>G	p.Ile798Arg	missense_variant	11/21	ENST00000397752.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MET	ENST00000397752.8	c.2393T>G	p.Ile798Arg	missense_variant	11/21	1	NM_000245.4	P3
MET	ENST00000318493.11	c.2447T>G	p.Ile816Arg	missense_variant	11/21	1		A2
MET	ENST00000436117.3	c.2293T>G	p.Ter765GluextTer11	stop_lost, NMD_transcript_variant	10/20	1
MET	ENST00000422097.2	c.2393T>G	p.Ile798Arg	missense_variant	11/12	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249064 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135096

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461752 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ExAC AF: 0.0000331 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal cell carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MET protein function. ClinVar contains an entry for this variant (Variation ID: 184921). This variant has not been reported in the literature in individuals affected with MET-related conditions. This variant is present in population databases (rs764960693, gnomAD 0.004%). This sequence change replaces isoleucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 816 of the MET protein (p.Ile816Arg). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2023

The p.I816R variant (also known as c.2447T>G), located in coding exon 10 of the MET gene, results from a T to G substitution at nucleotide position 2447. The isoleucine at codon 816 is replaced by arginine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Uncertain	23
Dann	Benign	0.80
DEOGEN2	Uncertain	0.43	T;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;D;D
MetaRNN	Uncertain	0.50	D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	1.7	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.98	T;T;T
Sift4G	Benign	0.58	T;T;D
Polyphen		0.73	P;B;.
Vest4		0.73
MutPred		0.64		Gain of disorder (P = 0.0149);.;.;
MVP		0.51
MPC		1.1
ClinPred		0.58	D
GERP RS		5.8
Varity_R		0.26
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs764960693; hg19: chr7-116403132;