rs4252120

Variant names:

• chr6-160722576-T-C
• rs4252120
• NM_000301.5:c.1256+9T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-160722576-T-C
• chr6-160722576-T-G

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.1256+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 1,609,930 control chromosomes in the GnomAD database, including 58,523 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4490 hom., cov: 32)
  • Exomes 𝑓: 0.26 (54033 hom.)
• Consequence: PLG NM_000301.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.666
• Publications: 70 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 6-160722576-T-C is Benign according to our data. Variant chr6-160722576-T-C is described in ClinVar as Benign. ClinVar VariationId is 1175041.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLG	NM_000301.5	MANE Select	c.1256+9T>C		intron	N/A	NP_000292.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLG	ENST00000308192.14	TSL:1 MANE Select	c.1256+9T>C		intron	N/A	ENSP00000308938.9
	PLG	ENST00000418964.2	TSL:4	c.1307+9T>C		intron	N/A	ENSP00000389424.2
	PLG	ENST00000297289.9	TSL:5	c.209+9T>C		intron	N/A	ENSP00000516619.1

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35207 AN: 151918 Hom.: 4490 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.222

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.246

GnomAD2 exomes AF: 0.215 AC: 53930 AN: 251306 AF XY: 0.217

Gnomad AFR exome AF: 0.178

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.291

Gnomad EAS exome AF: 0.000707

Gnomad FIN exome AF: 0.260

Gnomad NFE exome AF: 0.296

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.262 AC: 381619 AN: 1457894 Hom.: 54033 Cov.: 30 AF XY: 0.259 AC XY: 187574 AN XY: 725508

African (AFR) AF: 0.171 AC: 5710 AN: 33422

American (AMR) AF: 0.132 AC: 5887 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 7579 AN: 26100

East Asian (EAS) AF: 0.000529 AC: 21 AN: 39692

South Asian (SAS) AF: 0.108 AC: 9289 AN: 86208

European-Finnish (FIN) AF: 0.262 AC: 14011 AN: 53402

Middle Eastern (MID) AF: 0.257 AC: 1464 AN: 5698

European-Non Finnish (NFE) AF: 0.291 AC: 322750 AN: 1108396

Other (OTH) AF: 0.247 AC: 14908 AN: 60262

GnomAD4 genome AF: 0.232 AC: 35226 AN: 152036 Hom.: 4490 Cov.: 32 AF XY: 0.227 AC XY: 16887 AN XY: 74308

African (AFR) AF: 0.176 AC: 7280 AN: 41474

American (AMR) AF: 0.203 AC: 3102 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 1061 AN: 3468

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

South Asian (SAS) AF: 0.103 AC: 496 AN: 4820

European-Finnish (FIN) AF: 0.261 AC: 2754 AN: 10556

Middle Eastern (MID) AF: 0.216 AC: 63 AN: 292

European-Non Finnish (NFE) AF: 0.291 AC: 19747 AN: 67950

Other (OTH) AF: 0.244 AC: 512 AN: 2102

Alfa AF: 0.268 Hom.: 23221

Bravo AF: 0.228

Asia WGS AF: 0.0530 AC: 188 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	15
DANN	Benign	0.58
PhyloP100		0.67
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4252120; hg19: chr6-161143608; COSMIC: COSV51983668;