dbSNP rs4252170: PLG:p.Ala694Ala (chr6-160741374-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000301.5(PLG):c.2082T>C(p.Ala694Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0771 in 1,612,254 control chromosomes in the GnomAD database, including 5,221 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.063 ( 385 hom., cov: 33)

Exomes 𝑓: 0.078 ( 4836 hom. )

Consequence

PLG
NM_000301.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.02

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 6-160741374-T-C is Benign according to our data. Variant chr6-160741374-T-C is described in ClinVar as [Benign]. Clinvar id is 1268733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-160741374-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.02 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0904 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLG	NM_000301.5 link	c.2082T>C	p.Ala694Ala	synonymous_variant	Exon 17 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.2082T>C	p.Ala694Ala	synonymous_variant	Exon 17 of 19	1	NM_000301.5	ENSP00000308938.9		P00747

Frequencies

GnomAD3 genomes

AF:

0.0634

AC:

9653

AN:

152240

Hom.:

382

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0185

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.0651

Gnomad ASJ

AF:

0.0772

Gnomad EAS

AF:

0.0976

Gnomad SAS

AF:

0.0553

Gnomad FIN

AF:

0.0989

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0815

Gnomad OTH

AF:

0.0798

GnomAD3 exomes

AF:

0.0740

AC:

18616

AN:

251476

Hom.:

757

AF XY:

0.0742

AC XY:

10089

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.0183

Gnomad AMR exome

AF:

0.0554

Gnomad ASJ exome

AF:

0.0886

Gnomad EAS exome

AF:

0.0969

Gnomad SAS exome

AF:

0.0530

Gnomad FIN exome

AF:

0.101

Gnomad NFE exome

AF:

0.0824

Gnomad OTH exome

AF:

0.0902

GnomAD4 exome

AF:

0.0785

AC:

114579

AN:

1459896

Hom.:

4836

Cov.:

AF XY:

0.0775

AC XY:

56265

AN XY:

726420

show subpopulations

Gnomad4 AFR exome

AF:

0.0184

Gnomad4 AMR exome

AF:

0.0577

Gnomad4 ASJ exome

AF:

0.0863

Gnomad4 EAS exome

AF:

0.113

Gnomad4 SAS exome

AF:

0.0517

Gnomad4 FIN exome

AF:

0.0982

Gnomad4 NFE exome

AF:

0.0805

Gnomad4 OTH exome

AF:

0.0825

GnomAD4 genome

AF:

0.0634

AC:

9659

AN:

152358

Hom.:

385

Cov.:

AF XY:

0.0638

AC XY:

4753

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0185

Gnomad4 AMR

AF:

0.0651

Gnomad4 ASJ

AF:

0.0772

Gnomad4 EAS

AF:

0.0975

Gnomad4 SAS

AF:

0.0547

Gnomad4 FIN

AF:

0.0989

Gnomad4 NFE

AF:

0.0815

Gnomad4 OTH

AF:

0.0855

Alfa

AF:

0.0808

Hom.:

1332

Bravo

AF:

0.0592

Asia WGS

AF:

0.128

AC:

446

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.89

CADD

Benign

0.098

DANN

Benign

0.69

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

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