6-160702419-T-C

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.49+66T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0752 in 1,389,948 control chromosomes in the GnomAD database, including 4,883 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.056 (351 hom., cov: 33)
  • Exomes 𝑓: 0.078 (4532 hom.)
• Consequence: PLG NM_000301.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.165

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=-0.91).
• BP6: Variant 6-160702419-T-C is Benign according to our data. Variant chr6-160702419-T-C is described in ClinVar as [Benign]. Clinvar id is 1221071.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0876 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLG	NM_000301.5	c.49+66T>C		intron_variant		ENST00000308192.14
PLG	NM_001168338.1	c.49+66T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLG	ENST00000308192.14	c.49+66T>C		intron_variant		1	NM_000301.5	P1

Frequencies

GnomAD3 genomes AF: 0.0562 AC: 8556 AN: 152190 Hom.: 351 Cov.: 33

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0475

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.00912

Gnomad FIN AF: 0.0507

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0895

Gnomad OTH AF: 0.0501

GnomAD4 exome AF: 0.0775 AC: 95937 AN: 1237640 Hom.: 4532 AF XY: 0.0753 AC XY: 46982 AN XY: 623690

Gnomad4 AFR exome AF: 0.0180

Gnomad4 AMR exome AF: 0.0314

Gnomad4 ASJ exome AF: 0.0274

Gnomad4 EAS exome AF: 0.000583

Gnomad4 SAS exome AF: 0.0116

Gnomad4 FIN exome AF: 0.0597

Gnomad4 NFE exome AF: 0.0931

Gnomad4 OTH exome AF: 0.0626

GnomAD4 genome AF: 0.0562 AC: 8555 AN: 152308 Hom.: 351 Cov.: 33 AF XY: 0.0519 AC XY: 3868 AN XY: 74472

Gnomad4 AFR AF: 0.0218

Gnomad4 AMR AF: 0.0473

Gnomad4 ASJ AF: 0.0311

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.00892

Gnomad4 FIN AF: 0.0507

Gnomad4 NFE AF: 0.0895

Gnomad4 OTH AF: 0.0496

Alfa AF: 0.0685 Hom.: 64

Bravo AF: 0.0541

Asia WGS AF: 0.00982 AC: 35 AN: 3478

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

Nov 12, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.73
Dann	Benign	0.78

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: rs4252185; hg19: chr6-161123451; COSMIC: COSV51986024; COSMIC: COSV51986024;