NM_000245.4:c.3682G>A

Variant names:

• chr7-116783353-G-A
• rs121913671
• NM_000245.4:c.3682G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000245.4(MET):​c.3682G>A​(p.Asp1228Asn) 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. D1228D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• 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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a turn (size 3) in uniprot entity MET_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000245.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899
• PP5: Variant 7-116783353-G-A is Pathogenic according to our data. Variant chr7-116783353-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13884.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-116783353-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.3682G>A	p.Asp1228Asn	missense_variant	Exon 19 of 21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3736G>A	p.Asp1246Asn	missense_variant	Exon 19 of 21		NP_001120972.1
MET	NM_001324402.2	c.2392G>A	p.Asp798Asn	missense_variant	Exon 18 of 20		NP_001311331.1
MET	XM_011516223.2	c.3739G>A	p.Asp1247Asn	missense_variant	Exon 20 of 22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.3682G>A	p.Asp1228Asn	missense_variant	Exon 19 of 21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.3736G>A	p.Asp1246Asn	missense_variant	Exon 19 of 21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*1287G>A		non_coding_transcript_exon_variant	Exon 18 of 20	1		ENSP00000410980.2
MET	ENST00000436117.3	n.*1287G>A		3_prime_UTR_variant	Exon 18 of 20	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Papillary renal cell carcinoma type 1 Pathogenic:1

May 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	1.5	L;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.4	D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.81
MutPred		0.76		Loss of phosphorylation at Y1230 (P = 0.0828);.;
MVP		0.89
MPC		1.8
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.96
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs121913671; hg19: chr7-116423407; COSMIC: COSV59256021;