chr7-116778878-G-T

Variant names:

• chr7-116778878-G-T
• NM_000245.4:c.3443G>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_000245.4(MET):​c.3443G>T​(p.Arg1148Leu) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1148Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-116778878-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.2961616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.3443G>T	p.Arg1148Leu	missense_variant	Exon 17 of 21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3497G>T	p.Arg1166Leu	missense_variant	Exon 17 of 21		NP_001120972.1
MET	NM_001324402.2	c.2153G>T	p.Arg718Leu	missense_variant	Exon 16 of 20		NP_001311331.1
MET	XM_011516223.2	c.3500G>T	p.Arg1167Leu	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.3443G>T	p.Arg1148Leu	missense_variant	Exon 17 of 21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.3497G>T	p.Arg1166Leu	missense_variant	Exon 17 of 21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*1048G>T		non_coding_transcript_exon_variant	Exon 16 of 20	1		ENSP00000410980.2
MET	ENST00000436117.3	n.*1048G>T		3_prime_UTR_variant	Exon 16 of 20	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461762 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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1166L variant (also known as c.3497G>T), located in coding exon 16 of the MET gene, results from a G to T substitution at nucleotide position 3497. The arginine at codon 1166 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated 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	0.29
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.47	N;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.084
Sift	Benign	0.078	T;T
Sift4G	Uncertain	0.028	D;D
Polyphen		0.83	P;B
Vest4		0.57
MutPred		0.57		Loss of sheet (P = 0.1398);.;
MVP		0.37
MPC		2.1
ClinPred		0.81	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.81

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: chr7-116418932;