rs766190061

Positions:

• chr7-116796033-G-A
• chr7-116796033-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BP4

The NM_000245.4(MET):​c.4082G>A​(p.Cys1361Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.25

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.

• PM1: In a region_of_interest Interaction with RANBP9 (size 178) in uniprot entity MET_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000245.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.2889884).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.4082G>A	p.Cys1361Tyr	missense_variant	21/21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.4136G>A	p.Cys1379Tyr	missense_variant	21/21		NP_001120972.1
MET	NM_001324402.2	c.2792G>A	p.Cys931Tyr	missense_variant	20/20		NP_001311331.1
MET	XM_011516223.2	c.4139G>A	p.Cys1380Tyr	missense_variant	22/22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.4082G>A	p.Cys1361Tyr	missense_variant	21/21	1	NM_000245.4	ENSP00000380860	P3
MET	ENST00000318493.11	c.4136G>A	p.Cys1379Tyr	missense_variant	21/21	1		ENSP00000317272	A2
MET	ENST00000436117.3	c.*1687G>A		3_prime_UTR_variant, NMD_transcript_variant	20/20	1		ENSP00000410980

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249296 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135232

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: 0.0000464

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461740 Hom.: 0 Cov.: 57 AF XY: 0.00000413 AC XY: 3 AN XY: 727180

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: 0.0000187

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000827 AC: 1

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal cell carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1379 of the MET protein (p.Cys1379Tyr). This variant is present in population databases (rs766190061, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with MET-related conditions. ClinVar contains an entry for this variant (Variation ID: 582596). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 25, 2022

The p.C1379Y variant (also known as c.4136G>A), located in coding exon 20 of the MET gene, results from a G to A substitution at nucleotide position 4136. The cysteine at codon 1379 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	0.13
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.060	T;T
Sift4G	Benign	0.067	T;T
Polyphen		0.94	P;D
Vest4		0.50
MutPred		0.39		Gain of solvent accessibility (P = 0.1116);.;
MVP		0.52
MPC		2.1
ClinPred		0.74	D
GERP RS		5.1
Varity_R		0.25
gMVP		0.96

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: rs766190061; hg19: chr7-116436087;