rs4252129

Variant names:

• chr6-160731873-C-T
• rs4252129
• NM_000301.5:c.1567C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000301.5(PLG):​c.1567C>T​(p.Arg523Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,614,034 control chromosomes in the GnomAD database, including 164 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R523Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0074 (10 hom., cov: 32)
  • Exomes 𝑓: 0.012 (154 hom.)
• Consequence: PLG NM_000301.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.259
• Publications: 26 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 -16 ACMG points.

• BP6: Variant 6-160731873-C-T is Benign according to our data. Variant chr6-160731873-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 770367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00738 (1124/152270) while in subpopulation NFE AF = 0.0133 (902/68026). AF 95% confidence interval is 0.0125. There are 10 homozygotes in GnomAd4. There are 501 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR,AD gene

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.1567C>T	p.Arg523Trp	missense	Exon 12 of 19	NP_000292.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLG	ENST00000308192.14	TSL:1 MANE Select	c.1567C>T	p.Arg523Trp	missense	Exon 12 of 19	ENSP00000308938.9
	PLG	ENST00000418964.2	TSL:4	c.1618C>T	p.Arg540Trp	missense	Exon 12 of 19	ENSP00000389424.2
	PLG	ENST00000297289.9	TSL:5	c.520C>T	p.Arg174Trp	missense	Exon 4 of 11	ENSP00000516619.1

Frequencies

GnomAD3 genomes AF: 0.00739 AC: 1124 AN: 152152 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00657 AC: 1650 AN: 251260 AF XY: 0.00658

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00360

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.0123 AC: 18045 AN: 1461764 Hom.: 154 Cov.: 32 AF XY: 0.0119 AC XY: 8623 AN XY: 727192

African (AFR) AF: 0.00203 AC: 68 AN: 33478

American (AMR) AF: 0.00239 AC: 107 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86258

European-Finnish (FIN) AF: 0.00316 AC: 169 AN: 53416

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.0153 AC: 17042 AN: 1111902

Other (OTH) AF: 0.0102 AC: 617 AN: 60392

GnomAD4 genome AF: 0.00738 AC: 1124 AN: 152270 Hom.: 10 Cov.: 32 AF XY: 0.00673 AC XY: 501 AN XY: 74448

African (AFR) AF: 0.00229 AC: 95 AN: 41540

American (AMR) AF: 0.00386 AC: 59 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0133 AC: 902 AN: 68026

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.0114 Hom.: 54

Bravo AF: 0.00782

TwinsUK AF: 0.0167 AC: 62

ALSPAC AF: 0.0208 AC: 80

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0138 AC: 119

ExAC AF: 0.00677 AC: 822

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0130

EpiControl AF: 0.0114

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Plasminogen deficiency, type I;C5543503:Angioedema, hereditary, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.022	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.26
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.027
Sift	Benign	0.18	T
Sift4G	Benign	0.23	T
Polyphen		0.037	B
Vest4		0.13
MVP		0.61
MPC		0.24
ClinPred		0.035	T
GERP RS		1.3
Varity_R		0.33
gMVP		0.84
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.26		Position offset: 20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4252129; hg19: chr6-161152905; COSMIC: COSV99805236; COSMIC: COSV99805236;