rs6092

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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:7O:1

Conservation

PhyloP100: 0.344

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 13573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-101128436-G-A is described in Lovd as [Benign].

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/exons	MANE	UniProt
SERPINE1	NM_000602.5 linkuse as main transcript	c.43G>A	p.Ala15Thr	missense_variant	2/9	ENST00000223095.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINE1	ENST00000223095.5 linkuse as main transcript	c.43G>A	p.Ala15Thr	missense_variant	2/9	1	NM_000602.5	P1	P05121-1

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

GnomAD3 exomes

AF:

0.0952

AC:

23897

AN:

251022

Hom.:

1330

AF XY:

0.0991

AC XY:

13443

AN XY:

135670

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 SAS exome

AF:

0.112

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

Gnomad4 AFR exome

AF:

0.0159

Gnomad4 AMR exome

AF:

0.0702

Gnomad4 ASJ exome

AF:

0.118

Gnomad4 EAS exome

AF:

0.0794

Gnomad4 SAS exome

AF:

0.110

Gnomad4 FIN exome

AF:

0.0731

Gnomad4 NFE exome

AF:

0.113

Gnomad4 OTH exome

AF:

0.101

GnomAD4 genome

AF:

0.0807

AC:

12285

AN:

152214

Hom.:

665

Cov.:

AF XY:

0.0792

AC XY:

5894

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0191

Gnomad4 AMR

AF:

0.0708

Gnomad4 ASJ

AF:

0.118

Gnomad4 EAS

AF:

0.0873

Gnomad4 SAS

AF:

0.108

Gnomad4 FIN

AF:

0.0649

Gnomad4 NFE

AF:

0.117

Gnomad4 OTH

AF:

0.0997

Alfa

AF:

0.0999

Hom.:

410

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:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital plasminogen activator inhibitor type 1 deficiency

Pathogenic:1Benign:2Other:1

Likely benign, no assertion criteria provided	research	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2005	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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 provided, no classification provided	literature only	GeneReviews	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	Mar 12, 2023	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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

Uncertain:1

Uncertain significance, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Jun 29, 2021

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

SERPINE1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 18, 2020

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

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

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

MutationTaster

Benign

1.0

P;P

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

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

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