rs6092

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000602.5(SERPINE1):c.43G>A(p.Ala15Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,613,970 control chromosomes in the GnomAD database, including 9,254 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.081 ( 665 hom., cov: 32)

Exomes 𝑓: 0.11 ( 8589 hom. )

Consequence

SERPINE1
NM_000602.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1U:1B:8O:1

Conservation

PhyloP100: 0.344

Publications

92 publications found

Variant links:

Genes affected

SERPINE1 (HGNC:8583): (serpin family E member 1) This gene encodes a member of the serine proteinase inhibitor (serpin) superfamily. This member is the principal inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA), and hence is an inhibitor of fibrinolysis. The protein also functions as a component of innate antiviral immunity. Defects in this gene are the cause of plasminogen activator inhibitor-1 deficiency (PAI-1 deficiency), and high concentrations of the gene product are associated with thrombophilia. [provided by RefSeq, Aug 2020]

SERPINE1 Gene-Disease associations (from GenCC):

congenital plasminogen activator inhibitor type 1 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics

SERPINE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024650395).

BP6

Variant 7-101128436-G-A is Benign according to our data. Variant chr7-101128436-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 13573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINE1	NM_000602.5 link	c.43G>A	p.Ala15Thr	missense_variant	Exon 2 of 9	ENST00000223095.5	NP_000593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINE1	ENST00000223095.5 link	c.43G>A	p.Ala15Thr	missense_variant	Exon 2 of 9	1	NM_000602.5	ENSP00000223095.4

Frequencies

GnomAD3 genomes

AF:

0.0808

AC:

12283

AN:

152096

Hom.:

663

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0191

Gnomad AMI

AF:

0.177

Gnomad AMR

AF:

0.0710

Gnomad ASJ

AF:

0.118

Gnomad EAS

AF:

0.0871

Gnomad SAS

AF:

0.108

Gnomad FIN

AF:

0.0649

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.117

Gnomad OTH

AF:

0.0965

GnomAD2 exomes

AF:

0.0952

AC:

23897

AN:

251022

AF XY:

0.0991

show subpopulations

Gnomad AFR exome

AF:

0.0179

Gnomad AMR exome

AF:

0.0697

Gnomad ASJ exome

AF:

0.121

Gnomad EAS exome

AF:

0.0892

Gnomad FIN exome

AF:

0.0683

Gnomad NFE exome

AF:

0.113

Gnomad OTH exome

AF:

0.102

GnomAD4 exome

AF:

0.106

AC:

155622

AN:

1461756

Hom.:

8589

Cov.:

AF XY:

0.107

AC XY:

77992

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.0159

AC:

531

AN:

33478

American (AMR)

AF:

0.0702

AC:

3140

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.118

AC:

3090

AN:

26134

East Asian (EAS)

AF:

0.0794

AC:

3151

AN:

39700

South Asian (SAS)

AF:

0.110

AC:

9463

AN:

86258

European-Finnish (FIN)

AF:

0.0731

AC:

3898

AN:

53328

Middle Eastern (MID)

AF:

0.0943

AC:

544

AN:

5768

European-Non Finnish (NFE)

AF:

0.113

AC:

125717

AN:

1111980

Other (OTH)

AF:

0.101

AC:

6088

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

8235

16470

24706

32941

41176

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4532

9064

13596

18128

22660

<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:

0.0807

AC:

12285

AN:

152214

Hom.:

665

Cov.:

AF XY:

0.0792

AC XY:

5894

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0191

AC:

792

AN:

41542

American (AMR)

AF:

0.0708

AC:

1082

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.118

AC:

409

AN:

3472

East Asian (EAS)

AF:

0.0873

AC:

452

AN:

5180

South Asian (SAS)

AF:

0.108

AC:

523

AN:

4822

European-Finnish (FIN)

AF:

0.0649

AC:

688

AN:

10598

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.117

AC:

7937

AN:

68002

Other (OTH)

AF:

0.0997

AC:

211

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

584

1169

1753

2338

2922

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

304

456

608

760

<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:

0.101

Hom.:

1528

Bravo

AF:

0.0775

TwinsUK

AF:

0.113

AC:

418

ALSPAC

AF:

0.117

AC:

450

ESP6500AA

AF:

0.0229

AC:

101

ESP6500EA

AF:

0.117

AC:

1008

ExAC

AF:

0.0963

AC:

11693

Asia WGS

AF:

0.111

AC:

387

AN:

3478

EpiCase

AF:

0.118

EpiControl

AF:

0.114

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Uncertain:1Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital plasminogen activator inhibitor type 1 deficiency

Pathogenic:1Benign:3Other:1

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:research

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jan 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 12, 2023

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Susceptibility to severe coronavirus disease (COVID-19) due to an impaired coagulation process

Uncertain:1

Jun 29, 2021

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

Differences in coagulation-related proteins according to the genotype of patients with severe COVID-19 -

SERPINE1-related disorder

Benign:1

Aug 18, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 12856128, 20981092, 15182577, 15650551) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.4

PhyloP100

0.34

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.30

REVEL

Uncertain

0.36

Sift

Benign

0.29

Sift4G

Benign

0.56

Polyphen

0.28

Vest4

0.023

MPC

0.22

ClinPred

0.022

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.056

gMVP

0.38

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over