chr7-116777434-G-A

Position:

• chr7-116777434-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BP6

The NM_000245.4(MET):​c.3305G>A​(p.Gly1102Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.83

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 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.09563306).
• BP6: Variant 7-116777434-G-A is Benign according to our data. Variant chr7-116777434-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411888.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.3305G>A	p.Gly1102Asp	missense_variant	16/21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3359G>A	p.Gly1120Asp	missense_variant	16/21		NP_001120972.1
MET	NM_001324402.2	c.2015G>A	p.Gly672Asp	missense_variant	15/20		NP_001311331.1
MET	XM_011516223.2	c.3362G>A	p.Gly1121Asp	missense_variant	17/22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.3305G>A	p.Gly1102Asp	missense_variant	16/21	1	NM_000245.4	ENSP00000380860	P3
MET	ENST00000318493.11	c.3359G>A	p.Gly1120Asp	missense_variant	16/21	1		ENSP00000317272	A2
MET	ENST00000436117.3	c.*910G>A		3_prime_UTR_variant, NMD_transcript_variant	15/20	1		ENSP00000410980

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461566 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727116

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Renal cell carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 23, 2022

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. 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) performed at Invitae indicates that this missense variant is not expected to disrupt MET protein function. ClinVar contains an entry for this variant (Variation ID: 411888). 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 glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1120 of the MET protein (p.Gly1120Asp). -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.54
DEOGEN2	Uncertain	0.65	D;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.096	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.25	N;N
REVEL	Benign	0.22
Sift	Benign	0.58	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.19
MutPred		0.38		Gain of solvent accessibility (P = 0.0638);.;
MVP		0.41
MPC		0.32
ClinPred		0.19	T
GERP RS		3.2
Varity_R		0.20
gMVP		0.64

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: rs1060503533; hg19: chr7-116417488; COSMIC: COSV59260667; COSMIC: COSV59260667;