rs2859879

chr6-160739051-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000301.5(PLG):c.1878-17G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.651 in 1,613,234 control chromosomes in the GnomAD database, including 346,585 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (35435 hom., cov: 30)
  • Exomes 𝑓: 0.65 (311150 hom.)
• Consequence: PLG NM_000301.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.794

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-160739051-G-A is Benign according to our data. Variant chr6-160739051-G-A is described in ClinVar as [Benign]. Clinvar id is 1263884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-160739051-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLG	NM_000301.5	c.1878-17G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000308192.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLG	ENST00000308192.14	c.1878-17G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000301.5	P1

Frequencies

GnomAD3 genomes AF: 0.677 AC: 102653 AN: 151734 Hom.: 35395 Cov.: 30

Gnomad AFR AF: 0.789

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.723

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.576

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.673

Gnomad OTH AF: 0.687

GnomAD3 exomes AF: 0.604 AC: 151811 AN: 251444 Hom.: 47659 AF XY: 0.606 AC XY: 82306 AN XY: 135900

Gnomad AFR exome AF: 0.793

Gnomad AMR exome AF: 0.423

Gnomad ASJ exome AF: 0.707

Gnomad EAS exome AF: 0.475

Gnomad SAS exome AF: 0.510

Gnomad FIN exome AF: 0.579

Gnomad NFE exome AF: 0.672

Gnomad OTH exome AF: 0.634

GnomAD4 exome AF: 0.648 AC: 947553 AN: 1461380 Hom.: 311150 Cov.: 46 AF XY: 0.646 AC XY: 469450 AN XY: 727046

Gnomad4 AFR exome AF: 0.793

Gnomad4 AMR exome AF: 0.436

Gnomad4 ASJ exome AF: 0.711

Gnomad4 EAS exome AF: 0.474

Gnomad4 SAS exome AF: 0.514

Gnomad4 FIN exome AF: 0.581

Gnomad4 NFE exome AF: 0.670

Gnomad4 OTH exome AF: 0.656

GnomAD4 genome AF: 0.677 AC: 102737 AN: 151854 Hom.: 35435 Cov.: 30 AF XY: 0.668 AC XY: 49588 AN XY: 74210

Gnomad4 AFR AF: 0.789

Gnomad4 AMR AF: 0.565

Gnomad4 ASJ AF: 0.723

Gnomad4 EAS AF: 0.487

Gnomad4 SAS AF: 0.506

Gnomad4 FIN AF: 0.576

Gnomad4 NFE AF: 0.673

Gnomad4 OTH AF: 0.682

Alfa AF: 0.659 Hom.: 8952

Bravo AF: 0.680

Asia WGS AF: 0.472 AC: 1642 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Angioedema, hereditary, 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Plasminogen deficiency, type I Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.075
Dann	Benign	0.47

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

Other links and lift over

dbSNP: rs2859879; hg19: chr6-161160083; COSMIC: COSV57519018; COSMIC: COSV57519018;