rs2859879

Variant names:

• chr6-160739051-G-A
• rs2859879
• NM_000301.5:c.1878-17G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000301.5(PLG):​c.1878-17G>A variant causes a 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 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.794
• Publications: 13 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1263884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000301.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLG	NM_000301.5	MANE Select	c.1878-17G>A		intron	N/A	NP_000292.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLG	ENST00000308192.14	TSL:1 MANE Select	c.1878-17G>A		intron	N/A	ENSP00000308938.9
	PLG	ENST00000872438.1		c.2199-17G>A		intron	N/A	ENSP00000542497.1
	PLG	ENST00000872435.1		c.1986-17G>A		intron	N/A	ENSP00000542494.1

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

GnomAD2 exomes AF: 0.604 AC: 151811 AN: 251444 AF XY: 0.606

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 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

African (AFR) AF: 0.793 AC: 26564 AN: 33480

American (AMR) AF: 0.436 AC: 19512 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.711 AC: 18575 AN: 26130

East Asian (EAS) AF: 0.474 AC: 18818 AN: 39692

South Asian (SAS) AF: 0.514 AC: 44367 AN: 86248

European-Finnish (FIN) AF: 0.581 AC: 31011 AN: 53404

Middle Eastern (MID) AF: 0.709 AC: 4091 AN: 5768

European-Non Finnish (NFE) AF: 0.670 AC: 744986 AN: 1111572

Other (OTH) AF: 0.656 AC: 39629 AN: 60372

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

African (AFR) AF: 0.789 AC: 32678 AN: 41426

American (AMR) AF: 0.565 AC: 8623 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.723 AC: 2508 AN: 3470

East Asian (EAS) AF: 0.487 AC: 2497 AN: 5130

South Asian (SAS) AF: 0.506 AC: 2430 AN: 4802

European-Finnish (FIN) AF: 0.576 AC: 6063 AN: 10530

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.673 AC: 45688 AN: 67918

Other (OTH) AF: 0.682 AC: 1436 AN: 2106

Alfa AF: 0.659 Hom.: 8952

Bravo AF: 0.680

Asia WGS AF: 0.472 AC: 1642 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Angioedema, hereditary, 4 (1)
-	-	1	Plasminogen deficiency, type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.075
DANN	Benign	0.47
PhyloP100		-0.79
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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