rs786204102

Variant names:

• chr7-116777392-A-G
• rs786204102
• NM_000245.4:c.3263A>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000245.4(MET):​c.3263A>G​(p.His1088Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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 5 ACMG points.

• PM1: In a domain Protein kinase (size 267) in uniprot entity MET_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) in NM_000245.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.3263A>G	p.His1088Arg	missense_variant	Exon 16 of 21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3317A>G	p.His1106Arg	missense_variant	Exon 16 of 21		NP_001120972.1
MET	NM_001324402.2	c.1973A>G	p.His658Arg	missense_variant	Exon 15 of 20		NP_001311331.1
MET	XM_011516223.2	c.3320A>G	p.His1107Arg	missense_variant	Exon 17 of 22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.3263A>G	p.His1088Arg	missense_variant	Exon 16 of 21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.3317A>G	p.His1106Arg	missense_variant	Exon 16 of 21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*868A>G		non_coding_transcript_exon_variant	Exon 15 of 20	1		ENSP00000410980.2
MET	ENST00000436117.3	n.*868A>G		3_prime_UTR_variant	Exon 15 of 20	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal cell carcinoma Uncertain:1

Jun 20, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "deleterious"; PolyPhen-2: “possibly damaging”; Align-GVGD: "Class C0"). This sequence change replaces histidine with arginine at codon 1106 of the MET protein (p.His1106Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This sequence change has not been published in the literature and is not present in population databases. ClinVar contains an entry for this variant (Variation ID: 188147). In summary, this is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.41	N;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.7	D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0030	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.85
MutPred		0.78		Gain of methylation at H1088 (P = 0.0143);.;
MVP		0.79
MPC		0.98
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.87
gMVP		0.64

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: rs786204102; hg19: chr7-116417446;