7-116775060-G-T

Position:

• chr7-116775060-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_000245.4(MET):​c.3208G>T​(p.Val1070Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.09

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 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.3208G>T	p.Val1070Leu	missense_variant	15/21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3262G>T	p.Val1088Leu	missense_variant	15/21		NP_001120972.1
MET	NM_001324402.2	c.1918G>T	p.Val640Leu	missense_variant	14/20		NP_001311331.1
MET	XM_011516223.2	c.3265G>T	p.Val1089Leu	missense_variant	16/22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.3208G>T	p.Val1070Leu	missense_variant	15/21	1	NM_000245.4	ENSP00000380860	P3
MET	ENST00000318493.11	c.3262G>T	p.Val1088Leu	missense_variant	15/21	1		ENSP00000317272	A2
MET	ENST00000436117.3	c.*813G>T		3_prime_UTR_variant, NMD_transcript_variant	14/20	1		ENSP00000410980
MET	ENST00000454623.1	c.463G>T	p.Val155Leu	missense_variant	3/3	5		ENSP00000398140

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727236

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: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1088 of the MET protein (p.Val1088Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MET-related conditions. ClinVar contains an entry for this variant (Variation ID: 958823). 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 with a negative predictive value of 80%. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 11, 2023

The p.V1088L variant (also known as c.3262G>T), located in coding exon 14 of the MET gene, results from a G to T substitution at nucleotide position 3262. The valine at codon 1088 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly 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	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.69	N;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	1.4	N;N;D
REVEL	Uncertain	0.33
Sift	Benign	0.59	T;T;D
Sift4G	Benign	1.0	T;T;D
Polyphen		0.93	P;B;.
Vest4		0.62
MutPred		0.73		Gain of catalytic residue at V1070 (P = 0.157);.;.;
MVP		0.79
MPC		0.83
ClinPred		0.80	D
GERP RS		5.6
Varity_R		0.57
gMVP		0.59

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: rs760285693; hg19: chr7-116415114;