rs14224

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000301.5(PLG):c.771T>C(p.Cys257Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 1,600,012 control chromosomes in the GnomAD database, including 145,900 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 15487 hom., cov: 32)

Exomes 𝑓: 0.42 ( 130413 hom. )

Consequence

PLG
NM_000301.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.334

Publications

30 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 6-160716747-T-C is Benign according to our data. Variant chr6-160716747-T-C is described in ClinVar as [Benign]. Clinvar id is 1175116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.334 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLG	NM_000301.5 link	c.771T>C	p.Cys257Cys	synonymous_variant	Exon 7 of 19	ENST00000308192.14	NP_000292.1	P00747

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PLG	ENST00000308192.14 link	c.771T>C	p.Cys257Cys	synonymous_variant	Exon 7 of 19	1	NM_000301.5	ENSP00000308938.9	P00747
PLG	ENST00000418964.2 link	c.822T>C	p.Cys274Cys	synonymous_variant	Exon 7 of 19	4		ENSP00000389424.2	A6PVI2
PLG	ENST00000706906.1 link	n.771T>C		non_coding_transcript_exon_variant	Exon 7 of 19			ENSP00000516618.1	A0A9L9PYG2
PLG	ENST00000297289.9 link	c.50-5661T>C		intron_variant	Intron 1 of 10	5		ENSP00000516619.1	A0A9L9PXP2

Frequencies

GnomAD3 genomes

AF:

0.447

AC:

67863

AN:

151930

Hom.:

15484

Cov.:

show subpopulations

Gnomad AFR

AF:

0.530

Gnomad AMI

AF:

0.505

Gnomad AMR

AF:

0.375

Gnomad ASJ

AF:

0.496

Gnomad EAS

AF:

0.455

Gnomad SAS

AF:

0.445

Gnomad FIN

AF:

0.341

Gnomad MID

AF:

0.566

Gnomad NFE

AF:

0.424

Gnomad OTH

AF:

0.451

GnomAD2 exomes

AF:

0.414

AC:

104031

AN:

251182

AF XY:

0.418

show subpopulations

Gnomad AFR exome

AF:

0.529

Gnomad AMR exome

AF:

0.310

Gnomad ASJ exome

AF:

0.491

Gnomad EAS exome

AF:

0.441

Gnomad FIN exome

AF:

0.347

Gnomad NFE exome

AF:

0.419

Gnomad OTH exome

AF:

0.433

GnomAD4 exome

AF:

0.422

AC:

610359

AN:

1447964

Hom.:

130413

Cov.:

AF XY:

0.424

AC XY:

305521

AN XY:

721148

show subpopulations

African (AFR)

AF:

0.528

AC:

17520

AN:

33174

American (AMR)

AF:

0.318

AC:

14229

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.496

AC:

12913

AN:

26038

East Asian (EAS)

AF:

0.440

AC:

17436

AN:

39630

South Asian (SAS)

AF:

0.456

AC:

39253

AN:

86004

European-Finnish (FIN)

AF:

0.346

AC:

18485

AN:

53410

Middle Eastern (MID)

AF:

0.499

AC:

2860

AN:

5736

European-Non Finnish (NFE)

AF:

0.420

AC:

461303

AN:

1099310

Other (OTH)

AF:

0.440

AC:

26360

AN:

59950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

16881

33762

50643

67524

84405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.447

AC:

67907

AN:

152048

Hom.:

15487

Cov.:

AF XY:

0.443

AC XY:

32894

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.530

AC:

21976

AN:

41478

American (AMR)

AF:

0.375

AC:

5738

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.496

AC:

1721

AN:

3472

East Asian (EAS)

AF:

0.455

AC:

2349

AN:

5162

South Asian (SAS)

AF:

0.446

AC:

2143

AN:

4810

European-Finnish (FIN)

AF:

0.341

AC:

3602

AN:

10578

Middle Eastern (MID)

AF:

0.582

AC:

171

AN:

294

European-Non Finnish (NFE)

AF:

0.424

AC:

28799

AN:

67946

Other (OTH)

AF:

0.449

AC:

948

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1903

3805

5708

7610

9513

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.431

Hom.:

35272

Bravo

AF:

0.450

Asia WGS

AF:

0.420

AC:

1459

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Angioedema, hereditary, 4

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Plasminogen deficiency, type I

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.59

(source)

DANN

Benign

0.58

PhyloP100

-0.33

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs14224

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