NM_000301.5:c.1256+1647A>C

Variant names:

• chr6-160724214-A-C
• rs9456577
• NM_000301.5:c.1256+1647A>C

Variant summary

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

The NM_000301.5(PLG):​c.1256+1647A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 152,322 control chromosomes in the GnomAD database, including 66 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 0.023 (66 hom., cov: 33)
• Consequence: PLG NM_000301.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51
• Publications: 5 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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLG	NM_000301.5	c.1256+1647A>C		intron_variant	Intron 10 of 18	ENST00000308192.14	NP_000292.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLG	ENST00000308192.14	c.1256+1647A>C		intron_variant	Intron 10 of 18	1	NM_000301.5	ENSP00000308938.9
PLG	ENST00000418964.2	c.1307+1647A>C		intron_variant	Intron 10 of 18	4		ENSP00000389424.2
PLG	ENST00000297289.9	c.209+1647A>C		intron_variant	Intron 2 of 10	5		ENSP00000516619.1
PLG	ENST00000706906.1	n.1256+1647A>C		intron_variant	Intron 10 of 18			ENSP00000516618.1

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3488 AN: 152204 Hom.: 66 Cov.: 33

Gnomad AFR AF: 0.00535

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.0863

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.0245

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0289

Gnomad OTH AF: 0.0253

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

GnomAD4 genome AF: 0.0229 AC: 3487 AN: 152322 Hom.: 66 Cov.: 33 AF XY: 0.0223 AC XY: 1662 AN XY: 74488

African (AFR) AF: 0.00534 AC: 222 AN: 41580

American (AMR) AF: 0.0213 AC: 326 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.0865 AC: 449 AN: 5188

South Asian (SAS) AF: 0.0161 AC: 78 AN: 4830

European-Finnish (FIN) AF: 0.0245 AC: 260 AN: 10606

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0289 AC: 1968 AN: 68022

Other (OTH) AF: 0.0251 AC: 53 AN: 2114

Alfa AF: 0.0257 Hom.: 75

Bravo AF: 0.0225

Asia WGS AF: 0.0310 AC: 109 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.8
DANN	Benign	0.90
PhyloP100		1.5
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: rs9456577; hg19: chr6-161145246;