7-116778832-G-T

Variant names:

• chr7-116778832-G-T
• rs745437003
• NM_000245.4:c.3397G>T

Variant summary

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

The NM_000245.4(MET):​c.3397G>T​(p.Asp1133Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,770 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: 0.0000014 (0 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.15

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, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.3397G>T	p.Asp1133Tyr	missense_variant	Exon 17 of 21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3451G>T	p.Asp1151Tyr	missense_variant	Exon 17 of 21		NP_001120972.1
MET	NM_001324402.2	c.2107G>T	p.Asp703Tyr	missense_variant	Exon 16 of 20		NP_001311331.1
MET	XM_011516223.2	c.3454G>T	p.Asp1152Tyr	missense_variant	Exon 18 of 22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.3397G>T	p.Asp1133Tyr	missense_variant	Exon 17 of 21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.3451G>T	p.Asp1151Tyr	missense_variant	Exon 17 of 21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*1002G>T		non_coding_transcript_exon_variant	Exon 16 of 20	1		ENSP00000410980.2
MET	ENST00000436117.3	n.*1002G>T		3_prime_UTR_variant	Exon 16 of 20	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249210 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135178

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461770 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727204

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal cell carcinoma Uncertain:1

Feb 15, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with tyrosine at codon 1151 of the MET protein (p.Asp1151Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant has not been reported in the literature in individuals with MET-related conditions. 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"). 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

Feb 20, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D1151Y variant (also known as c.3451G>T), located in coding exon 16 of the MET gene, results from a G to T substitution at nucleotide position 3451. The aspartic acid at codon 1151 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is well 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	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	0.42	N;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.050	T;D
Polyphen		1.0	D;D
Vest4		0.79
MutPred		0.49		Loss of catalytic residue at D1133 (P = 0.0568);.;
MVP		0.91
MPC		2.1
ClinPred		0.89	D
GERP RS		5.5
Varity_R		0.92
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs745437003; hg19: chr7-116418886; COSMIC: COSV59258094; COSMIC: COSV59258094;