6-160702270-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000301.5(PLG):c.-35G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00755 in 1,608,996 control chromosomes in the GnomAD database, including 355 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.028 (165 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (190 hom.)
• Consequence: PLG NM_000301.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.92

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-160702270-G-A is Benign according to our data. Variant chr6-160702270-G-A is described in ClinVar as [Benign]. Clinvar id is 1248531.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0829 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLG	NM_000301.5	c.-35G>A		5_prime_UTR_variant	1/19	ENST00000308192.14
PLG	NM_001168338.1	c.-35G>A		5_prime_UTR_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLG	ENST00000308192.14	c.-35G>A		5_prime_UTR_variant	1/19	1	NM_000301.5	P1

Frequencies

GnomAD3 genomes AF: 0.0279 AC: 4247 AN: 152170 Hom.: 166 Cov.: 32

Gnomad AFR AF: 0.0854

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0187

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.00342

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.0109 AC: 2529 AN: 231250 Hom.: 80 AF XY: 0.00898 AC XY: 1126 AN XY: 125406

Gnomad AFR exome AF: 0.0910

Gnomad AMR exome AF: 0.0127

Gnomad ASJ exome AF: 0.0274

Gnomad EAS exome AF: 0.000408

Gnomad SAS exome AF: 0.00159

Gnomad FIN exome AF: 0.0000547

Gnomad NFE exome AF: 0.00360

Gnomad OTH exome AF: 0.0107

GnomAD4 exome AF: 0.00542 AC: 7902 AN: 1456708 Hom.: 190 Cov.: 31 AF XY: 0.00519 AC XY: 3763 AN XY: 724686

Gnomad4 AFR exome AF: 0.0876

Gnomad4 AMR exome AF: 0.0141

Gnomad4 ASJ exome AF: 0.0293

Gnomad4 EAS exome AF: 0.00212

Gnomad4 SAS exome AF: 0.00205

Gnomad4 FIN exome AF: 0.0000388

Gnomad4 NFE exome AF: 0.00221

Gnomad4 OTH exome AF: 0.0127

GnomAD4 genome AF: 0.0279 AC: 4251 AN: 152288 Hom.: 165 Cov.: 32 AF XY: 0.0263 AC XY: 1955 AN XY: 74450

Gnomad4 AFR AF: 0.0853

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.0271

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00341

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.00774 Hom.: 3

Bravo AF: 0.0326

Asia WGS AF: 0.00636 AC: 22 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 21, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	15
Dann	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs4252060; hg19: chr6-161123302;