8-42180023-C-G

Position:

chr8-42180023-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000930.5(PLAT):c.1266G>C(p.Glu422Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000373 in 1,610,232 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000038 ( 1 hom. )

Consequence

PLAT
NM_000930.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0800

Variant links:

Genes affected

PLAT (HGNC:9051): (plasminogen activator, tissue type) This gene encodes tissue-type plasminogen activator, a secreted serine protease that converts the proenzyme plasminogen to plasmin, a fibrinolytic enzyme. The encoded preproprotein is proteolytically processed by plasmin or trypsin to generate heavy and light chains. These chains associate via disulfide linkages to form the heterodimeric enzyme. This enzyme plays a role in cell migration and tissue remodeling. Increased enzymatic activity causes hyperfibrinolysis, which manifests as excessive bleeding, while decreased activity leads to hypofibrinolysis, which can result in thrombosis or embolism. Alternative splicing of this gene results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

PLAT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15492031).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PLAT	NM_000930.5 linkuse as main transcript	c.1266G>C	p.Glu422Asp	missense_variant	12/14	ENST00000220809.9	NP_000921.1
PLAT	NM_033011.4 linkuse as main transcript	c.1128G>C	p.Glu376Asp	missense_variant	11/13		NP_127509.1
PLAT	NM_001319189.2 linkuse as main transcript	c.999G>C	p.Glu333Asp	missense_variant	10/12		NP_001306118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLAT	ENST00000220809.9 linkuse as main transcript	c.1266G>C	p.Glu422Asp	missense_variant	12/14	1	NM_000930.5	ENSP00000220809	P1	P00750-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000574

AC:

AN:

243894

Hom.:

AF XY:

0.0000682

AC XY:

AN XY:

131980

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000296

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000399

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000377

AC:

AN:

1457870

Hom.:

Cov.:

AF XY:

0.0000442

AC XY:

AN XY:

724764

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000559

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.1266G>C (p.E422D) alteration is located in exon 12 (coding exon 11) of the PLAT gene. This alteration results from a G to C substitution at nucleotide position 1266, causing the glutamic acid (E) at amino acid position 422 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.58

D;D;.;.;T;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.68

.;T;T;T;T;T

M_CAP

Benign

0.059

MetaRNN

Benign

0.15

T;T;T;T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

0.47

N;N;.;.;.;.

MutationTaster

Benign

0.99

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.7

N;N;N;N;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.11

T;T;T;T;T;T

Sift4G

Benign

0.34

T;T;T;T;T;T

Polyphen

0.011

B;B;B;.;B;B

Vest4

0.15

MutPred

0.58

Gain of phosphorylation at S417 (P = 0.1989);Gain of phosphorylation at S417 (P = 0.1989);.;.;.;.;

MVP

0.82

MPC

0.16

ClinPred

0.062

GERP RS

0.86

Varity_R

0.30

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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