6-160712014-C-T

Variant names:

• chr6-160712014-C-T
• rs1853017
• ENST00000484367.5:n.2200C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000484367.5(PLG):​n.2200C>T variant causes a non coding transcript exon 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 ENST00000484367.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.817
• Publications: 6 publications found

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]

PLG Gene-Disease associations (from GenCC):

• hypoplasminogenemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• angioedema, hereditary, 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PLG	NM_000301.5	c.407+823C>T		intron_variant	Intron 4 of 18	ENST00000308192.14	NP_000292.1
PLG	NM_001168338.1	c.*819C>T		downstream_gene_variant			NP_001161810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLG	ENST00000308192.14	c.407+823C>T		intron_variant	Intron 4 of 18	1	NM_000301.5	ENSP00000308938.9

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

African (AFR) AF: 0.479 AC: 5779 AN: 12074

American (AMR) AF: 0.192 AC: 1219 AN: 6356

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 2523 AN: 7168

East Asian (EAS) AF: 0.000836 AC: 8 AN: 9574

South Asian (SAS) AF: 0.141 AC: 5571 AN: 39376

European-Finnish (FIN) AF: 0.257 AC: 2105 AN: 8190

Middle Eastern (MID) AF: 0.416 AC: 656 AN: 1578

European-Non Finnish (NFE) AF: 0.294 AC: 153867 AN: 523966

Other (OTH) AF: 0.285 AC: 6767 AN: 23720

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

African (AFR) AF: 0.486 AC: 20128 AN: 41438

American (AMR) AF: 0.261 AC: 3985 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 1267 AN: 3466

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5184

South Asian (SAS) AF: 0.147 AC: 707 AN: 4822

European-Finnish (FIN) AF: 0.264 AC: 2787 AN: 10550

Middle Eastern (MID) AF: 0.507 AC: 149 AN: 294

European-Non Finnish (NFE) AF: 0.302 AC: 20528 AN: 67960

Other (OTH) AF: 0.342 AC: 723 AN: 2112

Alfa AF: 0.270 Hom.: 1988

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
PhyloP100		0.82
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1853017; hg19: chr6-161133046;