rs1463245808

chr7-116700099-G-Achr7-116700099-G-Cchr7-116700099-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000245.4(MET):c.1015G>A(p.Asp339Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,296 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D339D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • 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: 7.76

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MET	NM_000245.4	c.1015G>A	p.Asp339Asn	missense_variant	2/21	ENST00000397752.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MET	ENST00000397752.8	c.1015G>A	p.Asp339Asn	missense_variant	2/21	1	NM_000245.4	P3
MET	ENST00000318493.11	c.1015G>A	p.Asp339Asn	missense_variant	2/21	1		A2
MET	ENST00000436117.3	c.1015G>A	p.Asp339Asn	missense_variant, NMD_transcript_variant	2/20	1
MET	ENST00000422097.2	c.1015G>A	p.Asp339Asn	missense_variant	2/12	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245888 Hom.: 0 AF XY: 0.00000750 AC XY: 1 AN XY: 133396

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: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458296 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725262

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.: 33

EpiCase AF: 0.0000546

EpiControl AF: 0.00

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

Invitae

Nov 13, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 339 of the MET protein (p.Asp339Asn). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 454173). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MET protein function. 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

Feb 12, 2022

The p.D339N variant (also known as c.1015G>A), located in coding exon 1 of the MET gene, results from a G to A substitution at nucleotide position 1015. The aspartic acid at codon 339 is replaced by asparagine, an amino acid with highly similar 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	0.20
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.7	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.013	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.35
MutPred		0.75		Loss of stability (P = 0.0539);Loss of stability (P = 0.0539);Loss of stability (P = 0.0539);
MVP		0.74
MPC		0.88
ClinPred		0.88	D
GERP RS		6.0
Varity_R		0.66
gMVP		0.66

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: rs1463245808; hg19: chr7-116340153;