rs1397743069

Positions:

• chr7-116775056-T-A
• chr7-116775056-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000245.4(MET):​c.3204T>A​(p.His1068Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar 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: -1.26

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3050759).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.3204T>A	p.His1068Gln	missense_variant	15/21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3258T>A	p.His1086Gln	missense_variant	15/21		NP_001120972.1
MET	NM_001324402.2	c.1914T>A	p.His638Gln	missense_variant	14/20		NP_001311331.1
MET	XM_011516223.2	c.3261T>A	p.His1087Gln	missense_variant	16/22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.3204T>A	p.His1068Gln	missense_variant	15/21	1	NM_000245.4	ENSP00000380860	P3
MET	ENST00000318493.11	c.3258T>A	p.His1086Gln	missense_variant	15/21	1		ENSP00000317272	A2
MET	ENST00000436117.3	c.*809T>A		3_prime_UTR_variant, NMD_transcript_variant	14/20	1		ENSP00000410980
MET	ENST00000454623.1	c.459T>A	p.His153Gln	missense_variant	3/3	5		ENSP00000398140

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 01, 2020

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MET-related disease. This sequence change replaces histidine with glutamine at codon 1086 of the MET protein (p.His1086Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.85	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.0	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.1	N;N;D
REVEL	Uncertain	0.47
Sift	Benign	0.035	D;D;D
Sift4G	Benign	0.10	T;T;D
Polyphen		1.0	D;P;.
Vest4		0.70
MutPred		0.34		Gain of loop (P = 0.2045);.;.;
MVP		0.86
MPC		0.89
ClinPred		0.63	D
GERP RS		-3.1
Varity_R		0.52
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1397743069; hg19: chr7-116415110;