rs2295368

chr6-160718470-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.950+14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 1,589,508 control chromosomes in the GnomAD database, including 125,115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10053 hom., cov: 32)
  • Exomes 𝑓: 0.40 (115062 hom.)
• Consequence: PLG NM_000301.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.79

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 6-160718470-G-A is Benign according to our data. Variant chr6-160718470-G-A is described in ClinVar as [Benign]. Clinvar id is 1174642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-160718470-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLG	NM_000301.5	c.950+14G>A		intron_variant		ENST00000308192.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLG	ENST00000308192.14	c.950+14G>A		intron_variant		1	NM_000301.5	P1
PLG	ENST00000297289.9	c.50-3938G>A		intron_variant		5
PLG	ENST00000418964.2	c.1001+14G>A		intron_variant		4
PLG	ENST00000706906.1	c.950+14G>A		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54068 AN: 151868 Hom.: 10051 Cov.: 32

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.411

Gnomad OTH AF: 0.357

GnomAD3 exomes AF: 0.374 AC: 94054 AN: 251162 Hom.: 18245 AF XY: 0.382 AC XY: 51893 AN XY: 135758

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.275

Gnomad ASJ exome AF: 0.411

Gnomad EAS exome AF: 0.441

Gnomad SAS exome AF: 0.409

Gnomad FIN exome AF: 0.344

Gnomad NFE exome AF: 0.404

Gnomad OTH exome AF: 0.386

GnomAD4 exome AF: 0.397 AC: 570281 AN: 1437522 Hom.: 115062 Cov.: 29 AF XY: 0.399 AC XY: 286083 AN XY: 716920

Gnomad4 AFR exome AF: 0.245

Gnomad4 AMR exome AF: 0.280

Gnomad4 ASJ exome AF: 0.411

Gnomad4 EAS exome AF: 0.439

Gnomad4 SAS exome AF: 0.411

Gnomad4 FIN exome AF: 0.343

Gnomad4 NFE exome AF: 0.406

Gnomad4 OTH exome AF: 0.392

GnomAD4 genome AF: 0.356 AC: 54084 AN: 151986 Hom.: 10053 Cov.: 32 AF XY: 0.355 AC XY: 26374 AN XY: 74298

Gnomad4 AFR AF: 0.258

Gnomad4 AMR AF: 0.318

Gnomad4 ASJ AF: 0.418

Gnomad4 EAS AF: 0.453

Gnomad4 SAS AF: 0.400

Gnomad4 FIN AF: 0.339

Gnomad4 NFE AF: 0.411

Gnomad4 OTH AF: 0.355

Alfa AF: 0.394 Hom.: 13720

Bravo AF: 0.348

Asia WGS AF: 0.382 AC: 1329 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

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	Nov 12, 2018	- -
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	-0.78
Cadd	Benign	0.11
Dann	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2295368; hg19: chr6-161139502; COSMIC: COSV51982891;