Variant rs780802614 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000245.4(MET):c.974C>A(p.Pro325His) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MET
NM_000245.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.75

Variant links:

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]

MET links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.41104323).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4 linkuse as main transcript	c.974C>A	p.Pro325His	missense_variant	2/21	ENST00000397752.8	NP_000236.2	P08581-1A0A024R759

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MET	ENST00000397752.8 linkuse as main transcript	c.974C>A	p.Pro325His	missense_variant	2/21	1	NM_000245.4	ENSP00000380860.3	P08581-1
MET	ENST00000318493.11 linkuse as main transcript	c.974C>A	p.Pro325His	missense_variant	2/21	1		ENSP00000317272.6	P08581-2
MET	ENST00000436117.3 linkuse as main transcript	n.974C>A		non_coding_transcript_exon_variant	2/20	1		ENSP00000410980.2	P08581-3
MET	ENST00000422097.2 linkuse as main transcript	c.974C>A	p.Pro325His	missense_variant	2/12	3		ENSP00000398776.2	H7C174

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248668

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134926

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

6.84e-7

AC:

AN:

1461358

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726990

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2024

The p.P325H variant (also known as c.974C>A), located in coding exon 1 of the MET gene, results from a C to A substitution at nucleotide position 974. The proline at codon 325 is replaced by histidine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;.;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.41

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.0

M;M;M

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.013

D;D;D

Sift4G

Uncertain

0.022

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.62

MutPred

0.57

Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);

MVP

0.45

MPC

0.91

ClinPred

0.94

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.62

gMVP

0.66

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over