rs14224

Variant names:

• chr6-160716747-T-C
• rs14224
• NM_000301.5:c.771T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000301.5(PLG):​c.771T>C​(p.Cys257Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 1,600,012 control chromosomes in the GnomAD database, including 145,900 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (15487 hom., cov: 32)
  • Exomes 𝑓: 0.42 (130413 hom.)
• Consequence: PLG NM_000301.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.334
• Publications: 30 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-160716747-T-C is Benign according to our data. Variant chr6-160716747-T-C is described in ClinVar as Benign. ClinVar VariationId is 1175116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.334 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.524 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLG	NM_000301.5	MANE Select	c.771T>C	p.Cys257Cys	synonymous	Exon 7 of 19	NP_000292.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLG	ENST00000308192.14	TSL:1 MANE Select	c.771T>C	p.Cys257Cys	synonymous	Exon 7 of 19	ENSP00000308938.9
	PLG	ENST00000418964.2	TSL:4	c.822T>C	p.Cys274Cys	synonymous	Exon 7 of 19	ENSP00000389424.2
	PLG	ENST00000706906.1		n.771T>C		non_coding_transcript_exon	Exon 7 of 19	ENSP00000516618.1

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67863 AN: 151930 Hom.: 15484 Cov.: 32

Gnomad AFR AF: 0.530

Gnomad AMI AF: 0.505

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.496

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.341

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.451

GnomAD2 exomes AF: 0.414 AC: 104031 AN: 251182 AF XY: 0.418

Gnomad AFR exome AF: 0.529

Gnomad AMR exome AF: 0.310

Gnomad ASJ exome AF: 0.491

Gnomad EAS exome AF: 0.441

Gnomad FIN exome AF: 0.347

Gnomad NFE exome AF: 0.419

Gnomad OTH exome AF: 0.433

GnomAD4 exome AF: 0.422 AC: 610359 AN: 1447964 Hom.: 130413 Cov.: 30 AF XY: 0.424 AC XY: 305521 AN XY: 721148

African (AFR) AF: 0.528 AC: 17520 AN: 33174

American (AMR) AF: 0.318 AC: 14229 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 12913 AN: 26038

East Asian (EAS) AF: 0.440 AC: 17436 AN: 39630

South Asian (SAS) AF: 0.456 AC: 39253 AN: 86004

European-Finnish (FIN) AF: 0.346 AC: 18485 AN: 53410

Middle Eastern (MID) AF: 0.499 AC: 2860 AN: 5736

European-Non Finnish (NFE) AF: 0.420 AC: 461303 AN: 1099310

Other (OTH) AF: 0.440 AC: 26360 AN: 59950

GnomAD4 genome AF: 0.447 AC: 67907 AN: 152048 Hom.: 15487 Cov.: 32 AF XY: 0.443 AC XY: 32894 AN XY: 74328

African (AFR) AF: 0.530 AC: 21976 AN: 41478

American (AMR) AF: 0.375 AC: 5738 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 1721 AN: 3472

East Asian (EAS) AF: 0.455 AC: 2349 AN: 5162

South Asian (SAS) AF: 0.446 AC: 2143 AN: 4810

European-Finnish (FIN) AF: 0.341 AC: 3602 AN: 10578

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.424 AC: 28799 AN: 67946

Other (OTH) AF: 0.449 AC: 948 AN: 2112

Alfa AF: 0.431 Hom.: 35272

Bravo AF: 0.450

Asia WGS AF: 0.420 AC: 1459 AN: 3476

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)
-	-	1	Angioedema, hereditary, 4 (1)
-	-	1	Plasminogen deficiency, type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.59
DANN	Benign	0.58
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs14224; hg19: chr6-161137779; COSMIC: COSV51980773; COSMIC: COSV51980773;