NM_000301.5:c.2126-2312A>G

Variant names:

• chr6-160749803-A-G
• rs783176
• NM_000301.5:c.2126-2312A>G

Variant summary

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

The NM_000301.5(PLG):​c.2126-2312A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 150,786 control chromosomes in the GnomAD database, including 2,462 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 0.16 (2462 hom., cov: 30)
• Consequence: PLG NM_000301.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62
• Publications: 11 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)

ENSG00000287558 (HGNC:):

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 (EAS) allele frequency at 95% confidence interval = 0.394 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.2126-2312A>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.2126-2312A>G		intron	N/A	ENSP00000308938.9
	PLG	ENST00000872438.1		c.2447-2312A>G		intron	N/A	ENSP00000542497.1
	PLG	ENST00000872435.1		c.2234-2312A>G		intron	N/A	ENSP00000542494.1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24236 AN: 150676 Hom.: 2461 Cov.: 30

Gnomad AFR AF: 0.0582

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.188

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.185

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

GnomAD4 genome AF: 0.161 AC: 24228 AN: 150786 Hom.: 2462 Cov.: 30 AF XY: 0.166 AC XY: 12228 AN XY: 73600

African (AFR) AF: 0.0580 AC: 2377 AN: 40970

American (AMR) AF: 0.182 AC: 2754 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 630 AN: 3456

East Asian (EAS) AF: 0.408 AC: 2077 AN: 5086

South Asian (SAS) AF: 0.313 AC: 1469 AN: 4694

European-Finnish (FIN) AF: 0.228 AC: 2374 AN: 10430

Middle Eastern (MID) AF: 0.185 AC: 53 AN: 286

European-Non Finnish (NFE) AF: 0.176 AC: 11940 AN: 67694

Other (OTH) AF: 0.192 AC: 401 AN: 2090

Alfa AF: 0.176 Hom.: 3061

Bravo AF: 0.152

Asia WGS AF: 0.373 AC: 1295 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.1
DANN	Benign	0.49
PhyloP100		1.6
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: rs783176; hg19: chr6-161170835;