chr6-160712014-C-T

Position:

• chr6-160712014-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000301.5(PLG):​c.407+823C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 784,020 control chromosomes in the GnomAD database, including 36,082 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.33 (9416 hom., cov: 31)
  • Exomes 𝑓: 0.28 (26666 hom.)
• Consequence: PLG NM_000301.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.817

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLG	NM_000301.5	c.407+823C>T		intron_variant		ENST00000308192.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLG	ENST00000308192.14	c.407+823C>T		intron_variant		1	NM_000301.5	P1

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50437 AN: 151900 Hom.: 9399 Cov.: 31

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.366

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.346

GnomAD4 exome AF: 0.282 AC: 178495 AN: 632002 Hom.: 26666 Cov.: 9 AF XY: 0.278 AC XY: 86562 AN XY: 311240

Gnomad4 AFR exome AF: 0.479

Gnomad4 AMR exome AF: 0.192

Gnomad4 ASJ exome AF: 0.352

Gnomad4 EAS exome AF: 0.000836

Gnomad4 SAS exome AF: 0.141

Gnomad4 FIN exome AF: 0.257

Gnomad4 NFE exome AF: 0.294

Gnomad4 OTH exome AF: 0.285

GnomAD4 genome AF: 0.332 AC: 50492 AN: 152018 Hom.: 9416 Cov.: 31 AF XY: 0.324 AC XY: 24053 AN XY: 74290

Gnomad4 AFR AF: 0.486

Gnomad4 AMR AF: 0.261

Gnomad4 ASJ AF: 0.366

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.147

Gnomad4 FIN AF: 0.264

Gnomad4 NFE AF: 0.302

Gnomad4 OTH AF: 0.342

Alfa AF: 0.251 Hom.: 1192

Bravo AF: 0.340

Asia WGS AF: 0.0950 AC: 332 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.1
DANN	Benign	0.52

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: rs1853017; hg19: chr6-161133046;