rs376235685

Positions:

• chr7-116700122-C-A
• chr7-116700122-C-G
• chr7-116700122-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000245.4(MET):​c.1038C>A​(p.Phe346Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.159

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.1038C>A	p.Phe346Leu	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.1038C>A	p.Phe346Leu	missense_variant	2/21	1	NM_000245.4	ENSP00000380860	P3
MET	ENST00000318493.11	c.1038C>A	p.Phe346Leu	missense_variant	2/21	1		ENSP00000317272	A2
MET	ENST00000436117.3	c.1038C>A	p.Phe346Leu	missense_variant, NMD_transcript_variant	2/20	1		ENSP00000410980
MET	ENST00000422097.2	c.1038C>A	p.Phe346Leu	missense_variant	2/12	3		ENSP00000398776

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;.;.
Eigen	Benign	0.075
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Pathogenic	3.4	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.3	D;D;D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.89
MutPred		0.88		Loss of methylation at K350 (P = 0.1366);Loss of methylation at K350 (P = 0.1366);Loss of methylation at K350 (P = 0.1366);
MVP		0.71
MPC		0.96
ClinPred		0.99	D
GERP RS		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-116340176;