rs1554398360

chr7-116771849-A-Gchr7-116771849-A-T

Variant summary

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

The NM_000245.4(MET):c.2888A>G(p.Asp963Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,500 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MET NM_000245.4 missense, splice_region
• Scores: Splicing: ADA: 0.7234
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.70

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.2888A>G	p.Asp963Gly	missense_variant, splice_region_variant	14/21	ENST00000397752.8
MET	NM_001127500.3	c.2942A>G	p.Asp981Gly	missense_variant, splice_region_variant	14/21
MET	NM_001324402.2	c.1598A>G	p.Asp533Gly	missense_variant, splice_region_variant	13/20
MET	XM_011516223.2	c.2945A>G	p.Asp982Gly	missense_variant, splice_region_variant	15/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MET	ENST00000397752.8	c.2888A>G	p.Asp963Gly	missense_variant, splice_region_variant	14/21	1	NM_000245.4	P3
MET	ENST00000318493.11	c.2942A>G	p.Asp981Gly	missense_variant, splice_region_variant	14/21	1		A2
MET	ENST00000436117.3	c.*493A>G		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	13/20	1
MET	ENST00000454623.1	c.283+195A>G		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461500 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727038

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Apr 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 12, 2022	The p.D981G variant (also known as c.2942A>G) is located in coding exon 13 of the MET gene. The aspartic acid at codon 981 is replaced by glycine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 13. This amino acid position is conserved. 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. -

Renal cell carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 28, 2023

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. ClinVar contains an entry for this variant (Variation ID: 454227). This variant has not been reported in the literature in individuals affected with MET-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 981 of the MET protein (p.Asp981Gly). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.60
Sift	Benign	0.060	T;T
Sift4G	Benign	0.19	T;T
Polyphen		1.0	D;D
Vest4		0.78
MutPred		0.52		Loss of stability (P = 0.0639);.;
MVP		0.77
MPC		1.0
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.46
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.72
dbscSNV1_RF	Benign	0.68
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: rs1554398360; hg19: chr7-116411903;