rs4252126

Variant names:

• chr6-160731262-A-G
• rs4252126
• NM_000301.5:c.1438+30A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-160731262-A-G
• chr6-160731262-A-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000301.5(PLG):​c.1438+30A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,567,980 control chromosomes in the GnomAD database, including 55,153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4000 hom., cov: 32)
  • Exomes 𝑓: 0.26 (51153 hom.)
• Consequence: PLG NM_000301.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.822
• Publications: 14 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: ClinGen, Orphanet, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-160731262-A-G is Benign according to our data. Variant chr6-160731262-A-G is described in ClinVar as Benign. ClinVar VariationId is 1245480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.287 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.1438+30A>G		intron	N/A	NP_000292.1	P00747

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLG	ENST00000308192.14	TSL:1 MANE Select	c.1438+30A>G		intron	N/A	ENSP00000308938.9	P00747
	PLG	ENST00000872438.1		c.1438+30A>G		intron	N/A	ENSP00000542497.1
	PLG	ENST00000872435.1		c.1438+30A>G		intron	N/A	ENSP00000542494.1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32130 AN: 152076 Hom.: 4004 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.223

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.290

Gnomad OTH AF: 0.228

GnomAD2 exomes AF: 0.209 AC: 52344 AN: 250586 AF XY: 0.213

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.291

Gnomad EAS exome AF: 0.000708

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.232

GnomAD4 exome AF: 0.258 AC: 364745 AN: 1415786 Hom.: 51153 Cov.: 24 AF XY: 0.255 AC XY: 180216 AN XY: 707122

African (AFR) AF: 0.0961 AC: 3127 AN: 32526

American (AMR) AF: 0.128 AC: 5713 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 7510 AN: 25864

East Asian (EAS) AF: 0.000531 AC: 21 AN: 39522

South Asian (SAS) AF: 0.107 AC: 9149 AN: 85460

European-Finnish (FIN) AF: 0.262 AC: 13975 AN: 53302

Middle Eastern (MID) AF: 0.254 AC: 1421 AN: 5600

European-Non Finnish (NFE) AF: 0.289 AC: 309636 AN: 1070012

Other (OTH) AF: 0.241 AC: 14193 AN: 58856

GnomAD4 genome AF: 0.211 AC: 32122 AN: 152194 Hom.: 4000 Cov.: 32 AF XY: 0.207 AC XY: 15390 AN XY: 74408

African (AFR) AF: 0.104 AC: 4319 AN: 41534

American (AMR) AF: 0.196 AC: 2990 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1059 AN: 3468

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5178

South Asian (SAS) AF: 0.102 AC: 492 AN: 4824

European-Finnish (FIN) AF: 0.262 AC: 2776 AN: 10604

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.290 AC: 19735 AN: 67982

Other (OTH) AF: 0.225 AC: 475 AN: 2110

Alfa AF: 0.266 Hom.: 7842

Bravo AF: 0.204

Asia WGS AF: 0.0460 AC: 164 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.27
DANN	Benign	0.34
PhyloP100		-0.82
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4252126;

hg19: chr6-161152294;

COSMIC: COSV51983676;

COSMIC: COSV51983676;