rs371939364

chr7-116763066-C-Achr7-116763066-C-Gchr7-116763066-C-T

Variant summary

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

The NM_000245.4(MET):c.2381C>A(p.Ser794Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. S794P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.55

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/exons	MANE	UniProt
MET	NM_000245.4	c.2381C>A	p.Ser794Tyr	missense_variant	11/21	ENST00000397752.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MET	ENST00000397752.8	c.2381C>A	p.Ser794Tyr	missense_variant	11/21	1	NM_000245.4	P3
MET	ENST00000318493.11	c.2435C>A	p.Ser812Tyr	missense_variant	11/21	1		A2
MET	ENST00000436117.3	c.2281C>A	p.Leu761Ile	missense_variant, NMD_transcript_variant	10/20	1
MET	ENST00000422097.2	c.2381C>A	p.Ser794Tyr	missense_variant	11/12	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal cell carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 22, 2020

This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with tyrosine at codon 812 of the MET protein (p.Ser812Tyr). The serine residue is moderately conserved and there is a large physicochemical difference between serine and tyrosine. 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 missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with MET-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Uncertain	26
Dann	Uncertain	0.99
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	-0.25	T
MutationTaster	Benign	1.0	D;D;N
PROVEAN	Benign	0.16	N
REVEL	Benign	0.17
Sift	Benign	0.83	T
Sift4G	Pathogenic	0.0	D
Vest4		0.47
MutPred		0.36		Gain of catalytic residue at L761 (P = 0.0722);
MVP		0.75
ClinPred		0.82	D
GERP RS		5.8

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-116403120;