rs786204142

Variant names:

• chr7-116759489-T-A
• NM_000245.4:c.2363T>A

Your query was ambiguous. Multiple possible variants found:

• chr7-116759489-T-A
• chr7-116759489-T-C
• chr7-116759489-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000245.4(MET):​c.2363T>A​(p.Val788Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MET NM_000245.4 missense, splice_region
• Scores: Splicing: ADA: 0.002219
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.10

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.2363T>A	p.Val788Glu	missense_variant, splice_region_variant	Exon 10 of 21	ENST00000397752.8	NP_000236.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.2363T>A	p.Val788Glu	missense_variant, splice_region_variant	Exon 10 of 21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.2417T>A	p.Val806Glu	missense_variant, splice_region_variant	Exon 10 of 21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.2264+869T>A		intron_variant	Intron 9 of 19	1		ENSP00000410980.2
MET	ENST00000422097.2	c.2363T>A	p.Val788Glu	missense_variant, splice_region_variant	Exon 10 of 12	3		ENSP00000398776.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 97 Uncertain:1

Nov 08, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 29, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V806E variant (also known as c.2417T>A), located in coding exon 9 of the MET gene, results from a T to A substitution at nucleotide position 2417. The valine at codon 806 is replaced by glutamic acid, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	0.32
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;.;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.5	L;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.060	N;N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.022	D;D;T
Sift4G	Benign	0.49	T;T;D
Polyphen		1.0	D;D;.
Vest4		0.84
MutPred		0.66		Gain of disorder (P = 0.0067);.;.;
MVP		0.80
MPC		1.2
ClinPred		0.78	D
GERP RS		4.7
Varity_R		0.39
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0022
dbscSNV1_RF	Benign	0.15
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-116399543;