rs6090

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.49G>A(p.Val17Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 1,614,080 control chromosomes in the GnomAD database, including 512 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 118 hom., cov: 32)

Exomes 𝑓: 0.015 ( 394 hom. )

Consequence

SERPINE1
NM_000602.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.62

Publications

23 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=0.0027550757).

BP6

Variant 7-101128442-G-A is Benign according to our data. Variant chr7-101128442-G-A is described in ClinVar as Benign. ClinVar VariationId is 358307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.061 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINE1	NM_000602.5 link	c.49G>A	p.Val17Ile	missense_variant	Exon 2 of 9	ENST00000223095.5	NP_000593.1	P05121-1A0A024QYT5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINE1	ENST00000223095.5 link	c.49G>A	p.Val17Ile	missense_variant	Exon 2 of 9	1	NM_000602.5	ENSP00000223095.4		P05121-1

Frequencies

GnomAD3 genomes

AF:

0.0327

AC:

4978

AN:

152130

Hom.:

118

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0631

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0313

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.0486

Gnomad SAS

AF:

0.0213

Gnomad FIN

AF:

0.0573

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0112

Gnomad OTH

AF:

0.0374

GnomAD2 exomes

AF:

0.0287

AC:

7211

AN:

251170

AF XY:

0.0261

show subpopulations

Gnomad AFR exome

AF:

0.0647

Gnomad AMR exome

AF:

0.0530

Gnomad ASJ exome

AF:

0.0175

Gnomad EAS exome

AF:

0.0512

Gnomad FIN exome

AF:

0.0598

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.0266

GnomAD4 exome

AF:

0.0154

AC:

22541

AN:

1461832

Hom.:

394

Cov.:

AF XY:

0.0151

AC XY:

10982

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.0650

AC:

2176

AN:

33480

American (AMR)

AF:

0.0499

AC:

2230

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

451

AN:

26136

East Asian (EAS)

AF:

0.0352

AC:

1398

AN:

39700

South Asian (SAS)

AF:

0.0154

AC:

1326

AN:

86258

European-Finnish (FIN)

AF:

0.0563

AC:

3005

AN:

53378

Middle Eastern (MID)

AF:

0.0251

AC:

145

AN:

5768

European-Non Finnish (NFE)

AF:

0.00949

AC:

10550

AN:

1111998

Other (OTH)

AF:

0.0209

AC:

1260

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1338

2677

4015

5354

6692

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

480

960

1440

1920

2400

<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:

0.0327

AC:

4981

AN:

152248

Hom.:

118

Cov.:

AF XY:

0.0345

AC XY:

2565

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0630

AC:

2617

AN:

41540

American (AMR)

AF:

0.0313

AC:

479

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

AN:

3470

East Asian (EAS)

AF:

0.0485

AC:

251

AN:

5178

South Asian (SAS)

AF:

0.0205

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0573

AC:

607

AN:

10592

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0112

AC:

759

AN:

68032

Other (OTH)

AF:

0.0379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

238

476

714

952

1190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0176

Hom.:

185

Bravo

AF:

0.0338

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.0672

AC:

296

ESP6500EA

AF:

0.00953

AC:

ExAC

AF:

0.0271

AC:

3289

Asia WGS

AF:

0.0440

AC:

153

AN:

3478

EpiCase

AF:

0.0114

EpiControl

AF:

0.0106

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital plasminogen activator inhibitor type 1 deficiency

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.0090

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.15

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.53

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.88

MutationAssessor

Benign

-0.26

PhyloP100

-1.6

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.010

REVEL

Benign

0.14

Sift

Benign

0.64

Sift4G

Benign

0.55

Polyphen

0.0

Vest4

0.0060

MPC

0.18

ClinPred

0.00030

GERP RS

-6.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.019

gMVP

0.095

Mutation Taster

=99/1

polymorphism (auto)

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over