rs4252120

Positions:

• chr6-160722576-T-C
• chr6-160722576-T-G

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.1256+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 1,609,930 control chromosomes in the GnomAD database, including 58,523 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4490 hom., cov: 32)
  • Exomes 𝑓: 0.26 (54033 hom.)
• Consequence: PLG NM_000301.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.666

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=-0.78).
• BP6: Variant 6-160722576-T-C is Benign according to our data. Variant chr6-160722576-T-C is described in ClinVar as [Benign]. Clinvar id is 1175041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-160722576-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLG	NM_000301.5	c.1256+9T>C		intron_variant		ENST00000308192.14	NP_000292.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLG	ENST00000308192.14	c.1256+9T>C		intron_variant		1	NM_000301.5	ENSP00000308938.9
PLG	ENST00000418964.2	c.1307+9T>C		intron_variant		4		ENSP00000389424.2
PLG	ENST00000297289.9	c.209+9T>C		intron_variant		5		ENSP00000516619.1
PLG	ENST00000706906.1	n.1256+9T>C		intron_variant				ENSP00000516618.1

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35207 AN: 151918 Hom.: 4490 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.222

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.246

GnomAD3 exomes AF: 0.215 AC: 53930 AN: 251306 Hom.: 7130 AF XY: 0.217 AC XY: 29440 AN XY: 135830

Gnomad AFR exome AF: 0.178

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.291

Gnomad EAS exome AF: 0.000707

Gnomad SAS exome AF: 0.102

Gnomad FIN exome AF: 0.260

Gnomad NFE exome AF: 0.296

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.262 AC: 381619 AN: 1457894 Hom.: 54033 Cov.: 30 AF XY: 0.259 AC XY: 187574 AN XY: 725508

Gnomad4 AFR exome AF: 0.171

Gnomad4 AMR exome AF: 0.132

Gnomad4 ASJ exome AF: 0.290

Gnomad4 EAS exome AF: 0.000529

Gnomad4 SAS exome AF: 0.108

Gnomad4 FIN exome AF: 0.262

Gnomad4 NFE exome AF: 0.291

Gnomad4 OTH exome AF: 0.247

GnomAD4 genome AF: 0.232 AC: 35226 AN: 152036 Hom.: 4490 Cov.: 32 AF XY: 0.227 AC XY: 16887 AN XY: 74308

Gnomad4 AFR AF: 0.176

Gnomad4 AMR AF: 0.203

Gnomad4 ASJ AF: 0.306

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.261

Gnomad4 NFE AF: 0.291

Gnomad4 OTH AF: 0.244

Alfa AF: 0.273 Hom.: 12518

Bravo AF: 0.228

Asia WGS AF: 0.0530 AC: 188 AN: 3478

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 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	15
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4252120; hg19: chr6-161143608; COSMIC: COSV51983668;