rs2020921

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000930.5(PLAT):c.490C>T(p.Arg164Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 1,603,474 control chromosomes in the GnomAD database, including 344 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R164Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 15 hom., cov: 33)

Exomes 𝑓: 0.019 ( 329 hom. )

Consequence

PLAT
NM_000930.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.15

Publications

32 publications found

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 Gene-Disease associations (from GenCC):

thrombophilia, familial, due to decreased release of tissue plasminogen activator
Inheritance: AR, AD Classification: MODERATE, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen

PLAT links:

ENSG00000304994 (HGNC:):

ENSG00000304994 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0053712428).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0127 (1942/152358) while in subpopulation NFE AF = 0.0217 (1477/68026). AF 95% confidence interval is 0.0208. There are 15 homozygotes in GnomAd4. There are 861 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLAT	NM_000930.5 link	c.490C>T	p.Arg164Trp	missense_variant	Exon 6 of 14	ENST00000220809.9	NP_000921.1	P00750-1
PLAT	NM_033011.4 link	c.352C>T	p.Arg118Trp	missense_variant	Exon 5 of 13		NP_127509.1	P00750-3
PLAT	NM_001319189.2 link	c.364+459C>T		intron_variant	Intron 5 of 11		NP_001306118.1	P00750B4DN26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLAT	ENST00000220809.9 link	c.490C>T	p.Arg164Trp	missense_variant	Exon 6 of 14	1	NM_000930.5	ENSP00000220809.4		P00750-1

Frequencies

GnomAD3 genomes

AF:

0.0128

AC:

1942

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00408

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00863

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00496

Gnomad FIN

AF:

0.00828

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0217

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.0122

AC:

2966

AN:

243878

AF XY:

0.0127

show subpopulations

Gnomad AFR exome

AF:

0.00359

Gnomad AMR exome

AF:

0.00528

Gnomad ASJ exome

AF:

0.00739

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00806

Gnomad NFE exome

AF:

0.0207

Gnomad OTH exome

AF:

0.0131

GnomAD4 exome

AF:

0.0193

AC:

27988

AN:

1451116

Hom.:

329

Cov.:

AF XY:

0.0189

AC XY:

13651

AN XY:

722126

show subpopulations

African (AFR)

AF:

0.00407

AC:

136

AN:

33440

American (AMR)

AF:

0.00574

AC:

256

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.00682

AC:

178

AN:

26100

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39662

South Asian (SAS)

AF:

0.00456

AC:

393

AN:

86098

European-Finnish (FIN)

AF:

0.00898

AC:

399

AN:

44430

Middle Eastern (MID)

AF:

0.0191

AC:

110

AN:

5766

European-Non Finnish (NFE)

AF:

0.0230

AC:

25515

AN:

1110754

Other (OTH)

AF:

0.0166

AC:

998

AN:

60234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

1365

2730

4096

5461

6826

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

982

1964

2946

3928

4910

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0127

AC:

1942

AN:

152358

Hom.:

Cov.:

AF XY:

0.0116

AC XY:

861

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.00406

AC:

169

AN:

41588

American (AMR)

AF:

0.00856

AC:

131

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00518

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00828

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0217

AC:

1477

AN:

68026

Other (OTH)

AF:

0.00851

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

108

217

325

434

542

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0204

Hom.:

931

Bravo

AF:

0.0121

TwinsUK

AF:

0.0229

AC:

ALSPAC

AF:

0.0236

AC:

ESP6500AA

AF:

0.00499

AC:

ESP6500EA

AF:

0.0222

AC:

191

ExAC

AF:

0.0121

AC:

1464

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0216

EpiControl

AF:

0.0211

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

T;T;.;T

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.83

.;T;T;T

MetaRNN

Benign

0.0054

T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.1

M;M;.;.

PhyloP100

1.1

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.8

D;D;D;D

REVEL

Benign

0.047

Sift

Benign

0.10

T;T;T;D

Sift4G

Uncertain

0.051

T;T;D;.

Polyphen

0.037

B;B;B;.

Vest4

0.13

MPC

0.24

ClinPred

0.044

GERP RS

1.9

Varity_R

0.27

gMVP

0.47

Mutation Taster

=80/20

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over