rs121913676

chr7-116783421-G-Achr7-116783421-G-Cchr7-116783421-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1 PM1 PM2 PM5 PP3_Moderate PP5

The NM_000245.4(MET):c.3750G>A(p.Met1250Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1250L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 13 ACMG points.

• PS1: Transcript NM_000245.4 (MET) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 376201
• PM1: In a domain Protein kinase (size 267) in uniprot entity MET_HUMAN there are 41 pathogenic changes around while only 16 benign (72%) in NM_000245.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-116783420-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376126.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891
• PP5: Variant 7-116783421-G-A is Pathogenic according to our data. Variant chr7-116783421-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13889.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-116783421-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MET	NM_000245.4	c.3750G>A	p.Met1250Ile	missense_variant	19/21	ENST00000397752.8
MET	NM_001127500.3	c.3804G>A	p.Met1268Ile	missense_variant	19/21
MET	NM_001324402.2	c.2460G>A	p.Met820Ile	missense_variant	18/20
MET	XM_011516223.2	c.3807G>A	p.Met1269Ile	missense_variant	20/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MET	ENST00000397752.8	c.3750G>A	p.Met1250Ile	missense_variant	19/21	1	NM_000245.4	P3
MET	ENST00000318493.11	c.3804G>A	p.Met1268Ile	missense_variant	19/21	1		A2
MET	ENST00000436117.3	c.*1355G>A		3_prime_UTR_variant, NMD_transcript_variant	18/20	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Dec 26, 2014

- -

Pediatric hepatocellular carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 15, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.86
MutPred		0.82		Gain of catalytic residue at L1255 (P = 0.0487);.;
MVP		0.86
MPC		2.0
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.97

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: rs121913676; hg19: chr7-116423475; COSMIC: COSV59268145;