rs4252105

chr6-160715026-T-Achr6-160715026-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000301.5(PLG):c.668+112T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 1,059,330 control chromosomes in the GnomAD database, including 81,153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (9921 hom., cov: 33)
  • Exomes 𝑓: 0.39 (71232 hom.)
• Consequence: PLG NM_000301.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.928

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-160715026-T-A is Benign according to our data. Variant chr6-160715026-T-A is described in ClinVar as [Benign]. Clinvar id is 1276813.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLG	NM_000301.5	c.668+112T>A		intron_variant		ENST00000308192.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLG	ENST00000308192.14	c.668+112T>A		intron_variant		1	NM_000301.5	P1
PLG	ENST00000297289.9	c.50-7382T>A		intron_variant		5
PLG	ENST00000418964.2	c.719+112T>A		intron_variant		4
PLG	ENST00000706906.1	c.668+112T>A		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53724 AN: 152020 Hom.: 9919 Cov.: 33

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.410

Gnomad OTH AF: 0.355

GnomAD4 exome AF: 0.391 AC: 354341 AN: 907192 Hom.: 71232 AF XY: 0.394 AC XY: 184393 AN XY: 467850

Gnomad4 AFR exome AF: 0.246

Gnomad4 AMR exome AF: 0.283

Gnomad4 ASJ exome AF: 0.408

Gnomad4 EAS exome AF: 0.437

Gnomad4 SAS exome AF: 0.412

Gnomad4 FIN exome AF: 0.319

Gnomad4 NFE exome AF: 0.402

Gnomad4 OTH exome AF: 0.383

GnomAD4 genome AF: 0.353 AC: 53740 AN: 152138 Hom.: 9921 Cov.: 33 AF XY: 0.351 AC XY: 26137 AN XY: 74392

Gnomad4 AFR AF: 0.257

Gnomad4 AMR AF: 0.318

Gnomad4 ASJ AF: 0.416

Gnomad4 EAS AF: 0.449

Gnomad4 SAS AF: 0.400

Gnomad4 FIN AF: 0.315

Gnomad4 NFE AF: 0.410

Gnomad4 OTH AF: 0.353

Alfa AF: 0.402 Hom.: 7134

Bravo AF: 0.348

Asia WGS AF: 0.381 AC: 1326 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.47
Dann	Benign	0.67

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: rs4252105; hg19: chr6-161136058;