rs4252125

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000301.5(PLG):c.1414G>A(p.Asp472Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 1,613,350 control chromosomes in the GnomAD database, including 58,614 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D472E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.23 ( 4498 hom., cov: 32)

Exomes 𝑓: 0.26 ( 54116 hom. )

Consequence

PLG
NM_000301.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0650

Publications

53 publications found

Variant links:

Genes affected

PLG (HGNC:9071): (plasminogen) The plasminogen protein encoded by this gene is a serine protease that circulates in blood plasma as an inactive zymogen and is converted to the active protease, plasmin, by several plasminogen activators such as tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), kallikrein, and factor XII (Hageman factor). The conversion of plasminogen to plasmin involves the cleavage of the peptide bond between Arg-561 and Val-562. Plasmin cleavage also releases the angiostatin protein which inhibits angiogenesis. Plasmin degrades many blood plasma proteins, including fibrin-containing blood clots. As a serine protease, plasmin cleaves many products in addition to fibrin such as fibronectin, thrombospondin, laminin, and von Willebrand factor. Plasmin is inactivated by proteins such as alpha-2-macroglobulin and alpha-2-antiplasmin in addition to inhibitors of the various plasminogen activators. Plasminogen also interacts with plasminogen receptors which results in the retention of plasmin on cell surfaces and in plasmin-induced cell signaling. The localization of plasminogen on cell surfaces plays a role in the degradation of extracellular matrices, cell migration, inflamation, wound healing, oncogenesis, metastasis, myogenesis, muscle regeneration, neurite outgrowth, and fibrinolysis. This protein may also play a role in acute respiratory distress syndrome (ARDS) which, in part, is caused by enhanced clot formation and the suppression of fibrinolysis. Compared to other mammals, the cluster of plasminogen-like genes to which this gene belongs has been rearranged in catarrhine primates. [provided by RefSeq, May 2020]

PLG Gene-Disease associations (from GenCC):

hypoplasminogenemia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
angioedema, hereditary, 4
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

PLG 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=0.0042169094).

BP6

Variant 6-160731208-G-A is Benign according to our data. Variant chr6-160731208-G-A is described in ClinVar as Benign. ClinVar VariationId is 692202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLG	NM_000301.5 link	c.1414G>A	p.Asp472Asn	missense_variant	Exon 11 of 19	ENST00000308192.14	NP_000292.1	P00747

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLG	ENST00000308192.14 link	c.1414G>A	p.Asp472Asn	missense_variant	Exon 11 of 19	1	NM_000301.5	ENSP00000308938.9		P00747

Frequencies

GnomAD3 genomes

AF:

0.232

AC:

35235

AN:

152058

Hom.:

4498

Cov.:

show subpopulations

Gnomad AFR

AF:

0.175

Gnomad AMI

AF:

0.223

Gnomad AMR

AF:

0.204

Gnomad ASJ

AF:

0.305

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.102

Gnomad FIN

AF:

0.262

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.290

Gnomad OTH

AF:

0.246

GnomAD2 exomes

AF:

0.215

AC:

53916

AN:

251298

AF XY:

0.217

show subpopulations

Gnomad AFR exome

AF:

0.178

Gnomad AMR exome

AF:

0.125

Gnomad ASJ exome

AF:

0.291

Gnomad EAS exome

AF:

0.000707

Gnomad FIN exome

AF:

0.259

Gnomad NFE exome

AF:

0.296

Gnomad OTH exome

AF:

0.234

GnomAD4 exome

AF:

0.262

AC:

383007

AN:

1461174

Hom.:

54116

Cov.:

AF XY:

0.259

AC XY:

188134

AN XY:

726904

show subpopulations

African (AFR)

AF:

0.171

AC:

5716

AN:

33462

American (AMR)

AF:

0.132

AC:

5885

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.290

AC:

7586

AN:

26124

East Asian (EAS)

AF:

0.000529

AC:

AN:

39700

South Asian (SAS)

AF:

0.107

AC:

9272

AN:

86252

European-Finnish (FIN)

AF:

0.262

AC:

14014

AN:

53414

Middle Eastern (MID)

AF:

0.258

AC:

1485

AN:

5758

European-Non Finnish (NFE)

AF:

0.292

AC:

324086

AN:

1111386

Other (OTH)

AF:

0.248

AC:

14942

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

13504

27007

40511

54014

67518

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10336

20672

31008

41344

51680

<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:

0.232

AC:

35254

AN:

152176

Hom.:

4498

Cov.:

AF XY:

0.227

AC XY:

16909

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.175

AC:

7288

AN:

41534

American (AMR)

AF:

0.203

AC:

3105

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.305

AC:

1060

AN:

3472

East Asian (EAS)

AF:

0.00174

AC:

AN:

5184

South Asian (SAS)

AF:

0.102

AC:

492

AN:

4826

European-Finnish (FIN)

AF:

0.262

AC:

2771

AN:

10580

Middle Eastern (MID)

AF:

0.218

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.290

AC:

19748

AN:

67982

Other (OTH)

AF:

0.244

AC:

514

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1380

2760

4140

5520

6900

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

362

724

1086

1448

1810

<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:

0.265

Hom.:

14285

Bravo

AF:

0.228

TwinsUK

AF:

0.304

AC:

1127

ALSPAC

AF:

0.288

AC:

1110

ESP6500AA

AF:

0.182

AC:

804

ESP6500EA

AF:

0.303

AC:

2604

ExAC

AF:

0.217

AC:

26356

Asia WGS

AF:

0.0540

AC:

190

AN:

3478

EpiCase

AF:

0.297

EpiControl

AF:

0.308

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 18566672, 15269832) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Otitis media, susceptibility to

Benign:1

Jul 26, 2019

Santos-Cortez Lab, University of Colorado School of Medicine

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.88

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.11

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0082

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0042

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.96

PhyloP100

-0.065

PrimateAI

Benign

0.26

PROVEAN

Benign

0.33

REVEL

Benign

0.063

Sift

Benign

0.40

Sift4G

Benign

0.50

Polyphen

0.0

Vest4

0.014

MPC

0.20

ClinPred

0.0014

GERP RS

2.1

Varity_R

0.032

gMVP

0.60

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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