rs73015965

Variant names:

• chr6-160706469-A-G
• rs73015965
• NM_000301.5:c.112A>G
• PLG p.Lys38Glu

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 12P and 6B. PS3 PP5_Very_Strong BP4 BS1_Supporting BS2

The NM_000301.5(PLG):​c.112A>G​(p.Lys38Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00498 in 1,613,830 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000538055: Functional studies have shown this variant causes decreased serum plasminogen activity and decreased plasminogen antigen levels (Schuster et al., 1999" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (34 hom.)
• Consequence: PLG NM_000301.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19 U:2 B:1
• Conservation: PhyloP100: 1.66
• Publications: 38 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, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
• angioedema, hereditary, 4

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000538055: Functional studies have shown this variant causes decreased serum plasminogen activity and decreased plasminogen antigen levels (Schuster et al., 1999; Schuster et al., 2001; Tefs et al., 2006).; SCV001142366: Functional studies have shown this variant causes decreased serum plasminogen activity and decreased plasminogen antigen levels (PMID: 16849641).; SCV004241800: At least one publication reports experimental evidence evaluating an impact on protein function and found that the secretion kinetics of the variant were normal, however, this study did not directly assess PLG activity (Tefs_2006).; SCV007096847: Coagulation studies revealed reduced plasminogen functional activity in individuals with type I plasminogen deficiency (PMID: 10233898).; SCV001553780: Functional in vitro data determined that secretion of mutant K38E protein from transfected cells was not significantly reduced (Tefs_2006_PMID:16849641).
• PP5: Variant 6-160706469-A-G is Pathogenic according to our data. Variant chr6-160706469-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 13583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19466236). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00277 (422/152322) while in subpopulation NFE AF = 0.00475 (323/68012). AF 95% confidence interval is 0.00432. There are 2 homozygotes in GnomAd4. There are 178 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLG	NM_000301.5	MANE Select	c.112A>G	p.Lys38Glu	missense	Exon 2 of 19	NP_000292.1	P00747
	PLG	NM_001168338.1		c.112A>G	p.Lys38Glu	missense	Exon 2 of 4	NP_001161810.1	Q5TEH5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLG	ENST00000308192.14	TSL:1 MANE Select	c.112A>G	p.Lys38Glu	missense	Exon 2 of 19	ENSP00000308938.9	P00747
	PLG	ENST00000366924.6	TSL:1	c.112A>G	p.Lys38Glu	missense	Exon 2 of 4	ENSP00000355891.2	Q5TEH5
	PLG	ENST00000484367.5	TSL:1	n.1082A>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 422 AN: 152204 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00475

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00295 AC: 742 AN: 251130 AF XY: 0.00280

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00280

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00513

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00521 AC: 7610 AN: 1461508 Hom.: 34 Cov.: 31 AF XY: 0.00493 AC XY: 3587 AN XY: 727074

African (AFR) AF: 0.000687 AC: 23 AN: 33466

American (AMR) AF: 0.00259 AC: 116 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86248

European-Finnish (FIN) AF: 0.000711 AC: 38 AN: 53420

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5736

European-Non Finnish (NFE) AF: 0.00651 AC: 7237 AN: 1111726

Other (OTH) AF: 0.00313 AC: 189 AN: 60370

GnomAD4 genome AF: 0.00277 AC: 422 AN: 152322 Hom.: 2 Cov.: 32 AF XY: 0.00239 AC XY: 178 AN XY: 74490

African (AFR) AF: 0.00125 AC: 52 AN: 41578

American (AMR) AF: 0.00196 AC: 30 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.000941 AC: 10 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00475 AC: 323 AN: 68012

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00418 Hom.: 0

Bravo AF: 0.00348

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00445

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	1	-	Plasminogen deficiency, type I (10)
8	-	-	not provided (8)
1	-	-	Angioedema, hereditary, 4 (1)
-	1	-	Deep venous thrombosis (1)
-	-	1	Otitis media, susceptibility to (1)
1	-	-	Plasminogen deficiency, type I;C5543503:Angioedema, hereditary, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.036	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.7
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.64
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.017	D
Varity_R		0.59
gMVP		0.61
Mutation Taster		=82/18	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs73015965;

hg19: chr6-161127501;

COSMIC: COSV51987550;