rs13231

chr6-160718825-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000301.5(PLG):c.1083A>G(p.Gln361=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,612,288 control chromosomes in the GnomAD database, including 57,749 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4403 hom., cov: 32)
  • Exomes 𝑓: 0.26 (53346 hom.)
• Consequence: PLG NM_000301.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.38

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.09).
• BP6: Variant 6-160718825-A-G is Benign according to our data. Variant chr6-160718825-A-G is described in ClinVar as [Benign]. Clinvar id is 1174953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-160718825-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLG	NM_000301.5	c.1083A>G	p.Gln361=	synonymous_variant	9/19	ENST00000308192.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLG	ENST00000308192.14	c.1083A>G	p.Gln361=	synonymous_variant	9/19	1	NM_000301.5	P1
PLG	ENST00000418964.2	c.1134A>G	p.Gln378=	synonymous_variant	9/19	4
PLG	ENST00000297289.9	c.50-3583A>G		intron_variant		5
PLG	ENST00000706906.1	c.1083A>G	p.Gln361=	synonymous_variant, NMD_transcript_variant	9/19

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34773 AN: 151998 Hom.: 4405 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.245

GnomAD3 exomes AF: 0.213 AC: 53322 AN: 250816 Hom.: 6982 AF XY: 0.215 AC XY: 29124 AN XY: 135540

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.000707

Gnomad SAS exome AF: 0.100

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.232

GnomAD4 exome AF: 0.260 AC: 379801 AN: 1460172 Hom.: 53346 Cov.: 34 AF XY: 0.257 AC XY: 186556 AN XY: 726472

Gnomad4 AFR exome AF: 0.165

Gnomad4 AMR exome AF: 0.131

Gnomad4 ASJ exome AF: 0.277

Gnomad4 EAS exome AF: 0.000529

Gnomad4 SAS exome AF: 0.106

Gnomad4 FIN exome AF: 0.261

Gnomad4 NFE exome AF: 0.290

Gnomad4 OTH exome AF: 0.245

GnomAD4 genome AF: 0.229 AC: 34781 AN: 152116 Hom.: 4403 Cov.: 32 AF XY: 0.224 AC XY: 16636 AN XY: 74350

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.201

Gnomad4 ASJ AF: 0.288

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.259

Gnomad4 NFE AF: 0.289

Gnomad4 OTH AF: 0.243

Alfa AF: 0.277 Hom.: 11608

Bravo AF: 0.225

Asia WGS AF: 0.0540 AC: 192 AN: 3478

EpiCase AF: 0.295

EpiControl AF: 0.307

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
Cadd	Benign	0.028
Dann	Benign	0.27

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: rs13231; hg19: chr6-161139857; COSMIC: COSV51983661;