rs4252109

Variant names:

• chr6-160716631-T-G
• rs4252109
• NM_000301.5:c.669-14T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000301.5(PLG):​c.669-14T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 1,419,248 control chromosomes in the GnomAD database, including 50,369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4409 hom., cov: 32)
  • Exomes 𝑓: 0.26 (45960 hom.)
• Consequence: PLG NM_000301.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.993
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 6-160716631-T-G is Benign according to our data. Variant chr6-160716631-T-G is described in ClinVar as Benign. ClinVar VariationId is 1175104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000301.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLG	NM_000301.5	MANE Select	c.669-14T>G		intron	N/A	NP_000292.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLG	ENST00000308192.14	TSL:1 MANE Select	c.669-14T>G		intron	N/A	ENSP00000308938.9
	PLG	ENST00000872438.1		c.669-14T>G		intron	N/A	ENSP00000542497.1
	PLG	ENST00000872435.1		c.669-14T>G		intron	N/A	ENSP00000542494.1

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34800 AN: 152010 Hom.: 4412 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.244

GnomAD2 exomes AF: 0.214 AC: 53652 AN: 251030 AF XY: 0.216

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.000708

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.233

GnomAD4 exome AF: 0.258 AC: 327187 AN: 1267120 Hom.: 45960 Cov.: 19 AF XY: 0.255 AC XY: 163607 AN XY: 641296

African (AFR) AF: 0.166 AC: 4956 AN: 29830

American (AMR) AF: 0.131 AC: 5813 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 6891 AN: 24888

East Asian (EAS) AF: 0.000515 AC: 20 AN: 38834

South Asian (SAS) AF: 0.114 AC: 9370 AN: 82282

European-Finnish (FIN) AF: 0.261 AC: 13934 AN: 53322

Middle Eastern (MID) AF: 0.257 AC: 1391 AN: 5422

European-Non Finnish (NFE) AF: 0.291 AC: 271650 AN: 934382

Other (OTH) AF: 0.245 AC: 13162 AN: 53676

GnomAD4 genome AF: 0.229 AC: 34806 AN: 152128 Hom.: 4409 Cov.: 32 AF XY: 0.224 AC XY: 16658 AN XY: 74368

African (AFR) AF: 0.169 AC: 7034 AN: 41514

American (AMR) AF: 0.201 AC: 3078 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1002 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5186

South Asian (SAS) AF: 0.107 AC: 516 AN: 4818

European-Finnish (FIN) AF: 0.260 AC: 2744 AN: 10574

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.289 AC: 19642 AN: 67956

Other (OTH) AF: 0.242 AC: 510 AN: 2110

Alfa AF: 0.271 Hom.: 8799

Bravo AF: 0.225

Asia WGS AF: 0.0550 AC: 194 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	16
DANN	Benign	0.63
PhyloP100		0.99
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: rs4252109; hg19: chr6-161137663; COSMIC: COSV51987571; COSMIC: COSV51987571;