rs45446492

chr7-116758548-G-Achr7-116758548-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000245.4(MET):c.2192G>A(p.Arg731Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,604 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R731R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.12

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 Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37480292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MET	NM_000245.4	c.2192G>A	p.Arg731Gln	missense_variant	9/21	ENST00000397752.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MET	ENST00000397752.8	c.2192G>A	p.Arg731Gln	missense_variant	9/21	1	NM_000245.4	P3
MET	ENST00000318493.11	c.2192G>A	p.Arg731Gln	missense_variant	9/21	1		A2
MET	ENST00000436117.3	c.2192G>A	p.Arg731Gln	missense_variant, NMD_transcript_variant	9/20	1
MET	ENST00000422097.2	c.2192G>A	p.Arg731Gln	missense_variant	9/12	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249238 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135218

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: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461604 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727102

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: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal cell carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 20, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 731 of the MET protein (p.Arg731Gln). This variant is present in population databases (rs45446492, gnomAD 0.006%). 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: 452678). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Papillary renal cell carcinoma type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

Jul 02, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 18, 2017

The R731Q variant in the MET gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R731Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R731Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position in the IPT/TIG2 domain where amino acids with similar properties to Arginine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R731Q as a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 28, 2022

The p.R731Q variant (also known as c.2192G>A), located in coding exon 8 of the MET gene, results from a G to A substitution at nucleotide position 2192. The arginine at codon 731 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly 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	0.17
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.;.;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Uncertain	0.077	D
MutationAssessor	Pathogenic	3.2	M;M;M;.
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.23	N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.17	T;T;D;D
Sift4G	Benign	0.54	T;T;D;D
Polyphen		0.99	D;D;.;.
Vest4		0.38
MutPred		0.51		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);.;
MVP		0.80
MPC		0.53
ClinPred		0.93	D
GERP RS		3.7
Varity_R		0.24
gMVP		0.86

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: rs45446492; hg19: chr7-116398602;