6-160732256-GA-G

Variant names:

• chr6-160732256-GA-G
• rs4252131
• NM_000301.5:c.1587+369delA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000301.5(PLG):​c.1587+369delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0324 in 152,188 control chromosomes in the GnomAD database, including 260 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.032 (260 hom., cov: 31)
• Consequence: PLG NM_000301.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.44
• Publications: 0 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLG	NM_000301.5	c.1587+369delA		intron_variant	Intron 12 of 18	ENST00000308192.14	NP_000292.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLG	ENST00000308192.14	c.1587+364delA		intron_variant	Intron 12 of 18	1	NM_000301.5	ENSP00000308938.9

Frequencies

GnomAD3 genomes AF: 0.0324 AC: 4923 AN: 152070 Hom.: 260 Cov.: 31

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.00952

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.0297

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0324 AC: 4926 AN: 152188 Hom.: 260 Cov.: 31 AF XY: 0.0310 AC XY: 2304 AN XY: 74426

African (AFR) AF: 0.108 AC: 4498 AN: 41498

American (AMR) AF: 0.0171 AC: 262 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00952 AC: 33 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68006

Other (OTH) AF: 0.0294 AC: 62 AN: 2112

Alfa AF: 0.0258 Hom.: 21

Bravo AF: 0.0367

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4
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: rs4252131; hg19: chr6-161153288;