rs4252129

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000301.5(PLG):c.1567C>T(p.Arg523Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,614,034 control chromosomes in the GnomAD database, including 164 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R523Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0074 ( 10 hom., cov: 32)

Exomes 𝑓: 0.012 ( 154 hom. )

Consequence

PLG
NM_000301.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.259

Publications

26 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 -16 ACMG points.

BP6

Variant 6-160731873-C-T is Benign according to our data. Variant chr6-160731873-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 770367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00738 (1124/152270) while in subpopulation NFE AF = 0.0133 (902/68026). AF 95% confidence interval is 0.0125. There are 10 homozygotes in GnomAd4. There are 501 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLG	NM_000301.5 link	c.1567C>T	p.Arg523Trp	missense_variant	Exon 12 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.1567C>T	p.Arg523Trp	missense_variant	Exon 12 of 19	1	NM_000301.5	ENSP00000308938.9		P00747

Frequencies

GnomAD3 genomes

AF:

0.00739

AC:

1124

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.0362

Gnomad AMR

AF:

0.00386

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0133

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00657

AC:

1650

AN:

251260

AF XY:

0.00658

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.00231

Gnomad ASJ exome

AF:

0.000894

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00360

Gnomad NFE exome

AF:

0.0124

Gnomad OTH exome

AF:

0.00555

GnomAD4 exome

AF:

0.0123

AC:

18045

AN:

1461764

Hom.:

154

Cov.:

AF XY:

0.0119

AC XY:

8623

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.00203

AC:

AN:

33478

American (AMR)

AF:

0.00239

AC:

107

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000689

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000209

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00316

AC:

169

AN:

53416

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0153

AC:

17042

AN:

1111902

Other (OTH)

AF:

0.0102

AC:

617

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

865

1731

2596

3462

4327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00738

AC:

1124

AN:

152270

Hom.:

Cov.:

AF XY:

0.00673

AC XY:

501

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00229

AC:

AN:

41540

American (AMR)

AF:

0.00386

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00235

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0133

AC:

902

AN:

68026

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

116

174

232

290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0114

Hom.:

Bravo

AF:

0.00782

TwinsUK

AF:

0.0167

AC:

ALSPAC

AF:

0.0208

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0138

AC:

119

ExAC

AF:

0.00677

AC:

822

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0130

EpiControl

AF:

0.0114

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PLG: BP4, BS1, BS2 -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Plasminogen deficiency, type I;C5543503:Angioedema, hereditary, 4

Benign:1

Aug 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.17

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.022

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0064

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

-0.26

PrimateAI

Benign

0.25

PROVEAN

Benign

-2.1

REVEL

Benign

0.027

Sift

Benign

0.18

Sift4G

Benign

0.23

Polyphen

0.037

Vest4

0.13

MVP

0.61

MPC

0.24

ClinPred

0.035

GERP RS

1.3

Varity_R

0.33

gMVP

0.84

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.26

Position offset: 20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs4252129

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