rs4252105

Variant names:

• chr6-160715026-T-A
• rs4252105
• NM_000301.5:c.668+112T>A

Your query was ambiguous. Multiple possible variants found:

• chr6-160715026-T-A
• chr6-160715026-T-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000301.5(PLG):​c.668+112T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 1,059,330 control chromosomes in the GnomAD database, including 81,153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (9921 hom., cov: 33)
  • Exomes 𝑓: 0.39 (71232 hom.)
• Consequence: PLG NM_000301.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.928
• Publications: 7 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• angioedema, hereditary, 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-160715026-T-A is Benign according to our data. Variant chr6-160715026-T-A is described in ClinVar as Benign. ClinVar VariationId is 1276813.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.434 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.668+112T>A		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.668+112T>A		intron	N/A	ENSP00000308938.9	P00747
	PLG	ENST00000872438.1		c.668+112T>A		intron	N/A	ENSP00000542497.1
	PLG	ENST00000872435.1		c.668+112T>A		intron	N/A	ENSP00000542494.1

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53724 AN: 152020 Hom.: 9919 Cov.: 33

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.410

Gnomad OTH AF: 0.355

GnomAD4 exome AF: 0.391 AC: 354341 AN: 907192 Hom.: 71232 AF XY: 0.394 AC XY: 184393 AN XY: 467850

African (AFR) AF: 0.246 AC: 5587 AN: 22704

American (AMR) AF: 0.283 AC: 10389 AN: 36756

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 9052 AN: 22196

East Asian (EAS) AF: 0.437 AC: 15109 AN: 34562

South Asian (SAS) AF: 0.412 AC: 28943 AN: 70282

European-Finnish (FIN) AF: 0.319 AC: 12565 AN: 39358

Middle Eastern (MID) AF: 0.318 AC: 1017 AN: 3202

European-Non Finnish (NFE) AF: 0.402 AC: 255620 AN: 636234

Other (OTH) AF: 0.383 AC: 16059 AN: 41898

GnomAD4 genome AF: 0.353 AC: 53740 AN: 152138 Hom.: 9921 Cov.: 33 AF XY: 0.351 AC XY: 26137 AN XY: 74392

African (AFR) AF: 0.257 AC: 10678 AN: 41504

American (AMR) AF: 0.318 AC: 4863 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1443 AN: 3468

East Asian (EAS) AF: 0.449 AC: 2321 AN: 5170

South Asian (SAS) AF: 0.400 AC: 1926 AN: 4816

European-Finnish (FIN) AF: 0.315 AC: 3340 AN: 10594

Middle Eastern (MID) AF: 0.305 AC: 89 AN: 292

European-Non Finnish (NFE) AF: 0.410 AC: 27872 AN: 67978

Other (OTH) AF: 0.353 AC: 746 AN: 2112

Alfa AF: 0.402 Hom.: 7134

Bravo AF: 0.348

Asia WGS AF: 0.381 AC: 1326 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.47
DANN	Benign	0.67
PhyloP100		-0.93
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: rs4252105; hg19: chr6-161136058;