7-116781989-A-G

Variant names:

• chr7-116781989-A-G
• NM_000245.4:c.3524A>G

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.3524A>G​(p.Asn1175Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000206 in 1,453,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MET NM_000245.4 missense, splice_region
• Scores: Splicing: ADA: 0.0003918
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.29

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 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=0.19253579).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.3524A>G	p.Asn1175Ser	missense_variant, splice_region_variant	Exon 18 of 21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3578A>G	p.Asn1193Ser	missense_variant, splice_region_variant	Exon 18 of 21		NP_001120972.1
MET	NM_001324402.2	c.2234A>G	p.Asn745Ser	missense_variant, splice_region_variant	Exon 17 of 20		NP_001311331.1
MET	XM_011516223.2	c.3581A>G	p.Asn1194Ser	missense_variant, splice_region_variant	Exon 19 of 22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.3524A>G	p.Asn1175Ser	missense_variant, splice_region_variant	Exon 18 of 21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.3578A>G	p.Asn1193Ser	missense_variant, splice_region_variant	Exon 18 of 21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*1129A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 20	1		ENSP00000410980.2
MET	ENST00000436117.3	n.*1129A>G		3_prime_UTR_variant	Exon 17 of 20	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453614 Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3 AN XY: 723774

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: 0.00000272

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal cell carcinoma Uncertain:1

Sep 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1193 of the MET protein (p.Asn1193Ser). 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. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Jul 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N1193S variant (also known as c.3578A>G), located in coding exon 17 of the MET gene, results from an A to G substitution at nucleotide position 3578. The asparagine at codon 1193 is replaced by serine, an amino acid with highly similar properties. This amino acid position is conserved. 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	0.069
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Uncertain	0.70	D;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.081
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.17	N;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Benign	0.28
Sift	Uncertain	0.017	D;D
Sift4G	Benign	0.089	T;T
Polyphen		0.022	B;B
Vest4		0.24
MutPred		0.36		Gain of disorder (P = 0.1314);.;
MVP		0.76
MPC		0.62
ClinPred		0.75	D
GERP RS		2.2
Varity_R		0.71
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00039
dbscSNV1_RF	Benign	0.018
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-116422043;