chr7-116700209-C-G

Position:

• chr7-116700209-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_000245.4(MET):​c.1125C>G​(p.Asn375Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000025 in 1,441,852 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N375S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000025 (1 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.826

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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11690968).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000025 (36/1441852) while in subpopulation EAS AF= 0.000909 (36/39606). AF 95% confidence interval is 0.000674. There are 1 homozygotes in gnomad4_exome. There are 14 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.1125C>G	p.Asn375Lys	missense_variant	2/21	ENST00000397752.8	NP_000236.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.1125C>G	p.Asn375Lys	missense_variant	2/21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.1125C>G	p.Asn375Lys	missense_variant	2/21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.1125C>G		non_coding_transcript_exon_variant	2/20	1		ENSP00000410980.2
MET	ENST00000422097.2	c.1125C>G	p.Asn375Lys	missense_variant	2/12	3		ENSP00000398776.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000219 AC: 5 AN: 228090 Hom.: 0 AF XY: 0.0000162 AC XY: 2 AN XY: 123374

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000295

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000250 AC: 36 AN: 1441852 Hom.: 1 Cov.: 32 AF XY: 0.0000195 AC XY: 14 AN XY: 716264

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000909

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.: 33

ExAC AF: 0.0000248 AC: 3

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 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

Oct 20, 2022

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 375 of the MET protein (p.Asn375Lys). This variant is present in population databases (rs776693512, gnomAD 0.03%). This missense change has been observed in individual(s) with lung cancer (PMID: 28294470). ClinVar contains an entry for this variant (Variation ID: 485743). 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. Experimental studies have shown that this missense change affects MET function (PMID: 28294470). 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

Jan 19, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate reduced proliferation capacity and impaired pathway activation (Tode et al., 2017); This variant is associated with the following publications: (PMID: 31342590, 28294470, 33854337) -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 02, 2024

This alteration is classified as 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	0.19
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.1
DANN	Benign	0.96
DEOGEN2	Benign	0.22	T;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.82	L;L;L
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.053
Sift	Benign	0.27	T;T;T
Sift4G	Benign	0.43	T;T;D
Polyphen		0.77	P;B;.
Vest4		0.32
MutPred		0.48		Gain of methylation at N375 (P = 0.0071);Gain of methylation at N375 (P = 0.0071);Gain of methylation at N375 (P = 0.0071);
MVP		0.34
MPC		0.50
ClinPred		0.039	T
GERP RS		1.3
Varity_R		0.22
gMVP		0.56

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: rs776693512; hg19: chr7-116340263;