chr6-160715262-G-A

Variant names:

• chr6-160715262-G-A
• rs9295131
• NM_000301.5:c.668+348G>A

Variant summary

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

The NM_000301.5(PLG):​c.668+348G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.584 in 152,010 control chromosomes in the GnomAD database, including 27,191 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 0.58 (27191 hom., cov: 32)
• Consequence: PLG NM_000301.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.427
• Publications: 10 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=-0.99).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.695 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLG	NM_000301.5	c.668+348G>A		intron_variant	Intron 6 of 18	ENST00000308192.14	NP_000292.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLG	ENST00000308192.14	c.668+348G>A		intron_variant	Intron 6 of 18	1	NM_000301.5	ENSP00000308938.9
PLG	ENST00000418964.2	c.719+348G>A		intron_variant	Intron 6 of 18	4		ENSP00000389424.2
PLG	ENST00000297289.9	c.50-7146G>A		intron_variant	Intron 1 of 10	5		ENSP00000516619.1
PLG	ENST00000706906.1	n.668+348G>A		intron_variant	Intron 6 of 18			ENSP00000516618.1

Frequencies

GnomAD3 genomes AF: 0.584 AC: 88748 AN: 151892 Hom.: 27184 Cov.: 32

Gnomad AFR AF: 0.427

Gnomad AMI AF: 0.731

Gnomad AMR AF: 0.520

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.500

Gnomad FIN AF: 0.598

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.700

Gnomad OTH AF: 0.599

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

GnomAD4 genome AF: 0.584 AC: 88769 AN: 152010 Hom.: 27191 Cov.: 32 AF XY: 0.578 AC XY: 42957 AN XY: 74296

African (AFR) AF: 0.426 AC: 17659 AN: 41452

American (AMR) AF: 0.519 AC: 7932 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 2447 AN: 3470

East Asian (EAS) AF: 0.451 AC: 2334 AN: 5170

South Asian (SAS) AF: 0.500 AC: 2406 AN: 4808

European-Finnish (FIN) AF: 0.598 AC: 6314 AN: 10560

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.700 AC: 47601 AN: 67962

Other (OTH) AF: 0.595 AC: 1255 AN: 2108

Alfa AF: 0.667 Hom.: 56651

Bravo AF: 0.572

Asia WGS AF: 0.433 AC: 1508 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.3
DANN	Benign	0.22
PhyloP100		0.43
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: rs9295131; hg19: chr6-161136294;