7-116796096-G-C

Position:

• chr7-116796096-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000245.4(MET):​c.4145G>C​(p.Arg1382Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.24

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.

• 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
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.123107105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.4145G>C	p.Arg1382Pro	missense_variant	21/21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.4199G>C	p.Arg1400Pro	missense_variant	21/21		NP_001120972.1
MET	NM_001324402.2	c.2855G>C	p.Arg952Pro	missense_variant	20/20		NP_001311331.1
MET	XM_011516223.2	c.4202G>C	p.Arg1401Pro	missense_variant	22/22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.4145G>C	p.Arg1382Pro	missense_variant	21/21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.4199G>C	p.Arg1400Pro	missense_variant	21/21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*1750G>C		non_coding_transcript_exon_variant	20/20	1		ENSP00000410980.2
MET	ENST00000436117.3	n.*1750G>C		3_prime_UTR_variant	20/20	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152164 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74454

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 97 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 25, 2023

- -

Renal cell carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 08, 2023

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1400 of the MET protein (p.Arg1400Pro). This variant is not present in population databases (gnomAD no frequency). 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: 569622). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 03, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2023

The p.R1400P variant (also known as c.4199G>C), located in coding exon 20 of the MET gene, results from a G to C substitution at nucleotide position 4199. The arginine at codon 1400 is replaced by proline, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. 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	0.095
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.33	T;.
Eigen	Benign	-0.088
Eigen_PC	Benign	0.087
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.47	T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.080	N;N
REVEL	Benign	0.26
Sift	Benign	0.24	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.11	B;B
Vest4		0.23
MutPred		0.27		Gain of catalytic residue at R1382 (P = 0.0407);.;
MVP		0.35
MPC		1.1
ClinPred		0.82	D
GERP RS		5.2
Varity_R		0.30
gMVP		0.59

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: rs752694306; hg19: chr7-116436150;