rs4252159

Variant names:

• chr6-160739612-G-A
• rs4252159
• NM_000301.5:c.2018+404G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-160739612-G-A
• chr6-160739612-G-T

Variant summary

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

The NM_000301.5(PLG):​c.2018+404G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0628 in 151,566 control chromosomes in the GnomAD database, including 380 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 0.063 (380 hom., cov: 30)
• Consequence: PLG NM_000301.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.365
• Publications: 4 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLG	NM_000301.5	c.2018+404G>A		intron_variant	Intron 16 of 18	ENST00000308192.14	NP_000292.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLG	ENST00000308192.14	c.2018+404G>A		intron_variant	Intron 16 of 18	1	NM_000301.5	ENSP00000308938.9

Frequencies

GnomAD3 genomes AF: 0.0628 AC: 9507 AN: 151448 Hom.: 378 Cov.: 30

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.0584

Gnomad AMR AF: 0.0654

Gnomad ASJ AF: 0.0817

Gnomad EAS AF: 0.0979

Gnomad SAS AF: 0.0504

Gnomad FIN AF: 0.0994

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0815

Gnomad OTH AF: 0.0813

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

GnomAD4 genome AF: 0.0628 AC: 9512 AN: 151566 Hom.: 380 Cov.: 30 AF XY: 0.0632 AC XY: 4682 AN XY: 74066

African (AFR) AF: 0.0162 AC: 670 AN: 41378

American (AMR) AF: 0.0653 AC: 995 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.0817 AC: 282 AN: 3452

East Asian (EAS) AF: 0.0977 AC: 503 AN: 5146

South Asian (SAS) AF: 0.0498 AC: 239 AN: 4800

European-Finnish (FIN) AF: 0.0994 AC: 1032 AN: 10378

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0815 AC: 5530 AN: 67870

Other (OTH) AF: 0.0866 AC: 182 AN: 2102

Alfa AF: 0.0740 Hom.: 722

Bravo AF: 0.0583

Asia WGS AF: 0.128 AC: 446 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.72
DANN	Benign	0.41
PhyloP100		0.36
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: rs4252159; hg19: chr6-161160644;