6-160706469-A-G

Position:

• chr6-160706469-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP5 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (34 hom.)
• Consequence: PLG NM_000301.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13 U:3 B:1
• Conservation: PhyloP100: 1.66

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 Likely_benign. Variant got -5 ACMG points.

• PP5: Variant 6-160706469-A-G is Pathogenic according to our data. Variant chr6-160706469-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13583.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=8, Uncertain_significance=3}. Variant chr6-160706469-A-G is described in Lovd as [Pathogenic]. Variant chr6-160706469-A-G is described in Lovd as [Likely_pathogenic].
• 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_exome allele frequency = 0.00521 (7610/1461508) while in subpopulation NFE AF= 0.00651 (7237/1111726). AF 95% confidence interval is 0.00638. There are 34 homozygotes in gnomad4_exome. There are 3587 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLG	NM_000301.5	c.112A>G	p.Lys38Glu	missense_variant	2/19	ENST00000308192.14
PLG	NM_001168338.1	c.112A>G	p.Lys38Glu	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLG	ENST00000308192.14	c.112A>G	p.Lys38Glu	missense_variant	2/19	1	NM_000301.5	P1

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

GnomAD3 exomes AF: 0.00295 AC: 742 AN: 251130 Hom.: 4 AF XY: 0.00280 AC XY: 380 AN XY: 135720

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 SAS exome AF: 0.0000653

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

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00259

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000711

Gnomad4 NFE exome AF: 0.00651

Gnomad4 OTH exome AF: 0.00313

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

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00475

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00453 Hom.: 0

Bravo AF: 0.00348

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00330 AC: 400

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00445

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13 Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Plasminogen deficiency, type I Pathogenic:7 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 01, 2023	Variant summary: PLG c.112A>G (p.Lys38Glu) results in a conservative amino acid change located in the PAN/Apple domain (IPR003609) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.003 in 251130 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in PLG causing Plasminogen Deficiency phenotype (0.0011), suggesting that the variant could be benign. However, c.112A>G has been reported in the literature as a biallelic genotype in many individuals affected with Plasminogen Deficiency/Ligneous Conjuctivitis, including cases where it has been found in trans with loss of function variants and it has been found to segregate with disease in multiple unrelated families (e.g. Schuster_1999, Tefs_2006). These data indicate that the variant is very likely to be associated with disease. 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). The following publications have been ascertained in the context of this evaluation (PMID: 10233898, 16849641). Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Ten submitters classified the variant as pathogenic/likely pathogenic, one submitter classified it as uncertain significance and one as benign. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jan 27, 2016	The c.112A>G (p.Lys38Glu) missense variant in the PLG gene has been previously reported in numerous affected individuals with autosomal recessive Plasminogen Deficiency and has been shown to segregate with disease in affected family members (Schuster et al., 1999; Schuster et al., 2001). This variant has been observed in affected individuals in trans with multiple variants (Cys122Ter, Arg134Lys, Arg513His, Arg216His, and Leu128Pro) (Schuster et al., 1999; Schuster et al., 2001). 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). Case-control studies have found this variant to be significantly more prevalent in affected individuals relative to controls (Tefs et al., 2006). This c.112A>G has been reported in the three population databases at a frequency lower than the prevalence of the disease (Exome Sequencing Project [ESP] = 0.616%, 1000 Genomes = 1%, and ExAC = 0.496%). The PLG gene is the only gene in which mutations are known to cause Plasminogen Deficiency. Therefore, this collective evidence supports the classification of the c.112A>G (p.Lys38Glu) as a recessive Pathogenic variant for Plasminogen Deficiency. -
Likely pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000301.3:c.112A>G in the PLG gene has an allele frequency of 0.005 in European (non-Finnish) subpopulation in the gnomAD database. This variant has been observed in affected individuals in trans with multiple variants (Cys122Ter, Arg134Lys, Arg513His, Arg216His, and Leu128Pro) (PMID: 10233898; 12850227). Functional studies have shown this variant causes decreased serum plasminogen activity and decreased plasminogen antigen levels (PMID: 16849641). Case-control studies have found this variant to be significantly more prevalent in affected individuals relative to controls (PMID: 16849641). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3_VeryStrong; PS3; PS4; PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

not provided Pathogenic:6 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 06, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2022	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as K19E using alternate nomenclature; This variant is associated with the following publications: (PMID: 22995991, 27976734, 28876531, 20981092, 10233898, 30487145, 12850227, 26340456, 12945885, 23629776, 15269832, 16849641, 31980526, 31589614, 12876630, 34426522) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 09, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PLG p.Lys38Glu variant was found in 13 families in Scotland who were identified to have type I plasminogen deficiency (hypoplasminogenaemia) upon donating blood; the variant was reported to be the most common cause of hypoplasminogenaemia in Scotland, with a prevalence of 0.14% (Tefs_2003_PMID:12945885). Three unrelated patients with ligneous conjunctivitis were found to be compound heterozygous for the p.K38E variant; two of these patients presented in infancy while the third patient did not present until age 69. The two patients presenting in infancy both inherited the p.K38E variant from their unaffected fathers. Plasminogen antigen and activity levels were tested in these patients as well as their families; all three compound heterozygous patients with the p.K38E variant had little to no plasminogen antigen or activity, and the two p.K38E heterozygous carriers had decreased activity compared to wildtype (Schuster_1999_PMID:10233898). The variant was identified in dbSNP (ID: rs73015965), ClinVar (classified as pathogenic by Fulgent Genetics, EGL Genetics and Knight Diagnostic Laboratories, Oregon Health and Sciences University and as likely pathogenic by NIHR Bioresource Rare Diseases, University of Cambridge) and LOVD 3.0 (classified as a VUS and pathogenic). The variant was identified in control databases in 817 of 282530 chromosomes (4 homozygous) at a frequency of 0.002892 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 645 of 128850 chromosomes (freq: 0.005006), Other in 24 of 7220 chromosomes (freq: 0.003324), Latino in 99 of 35438 chromosomes (freq: 0.002794), African in 34 of 24962 chromosomes (freq: 0.001362), European (Finnish) in 13 of 25122 chromosomes (freq: 0.000518) and South Asian in 2 of 30616 chromosomes (freq: 0.000065), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Lys38 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. One study identified 6 type I plasminogen deficiency patients with homozygous K38E mutations that had a milder clinical course and higher residual plasminogen antigen and activity levels than patients with other plasminogen mutations; a homozygous K38E mutation (and similarly decreased PLG values) was also found in one patient's healthy brother, suggesting incomplete penetrance (Tefs_2006_PMID:16849641). Functional in vitro data determined that secretion of mutant K38E protein from transfected cells was not significantly reduced (Tefs_2006_PMID:16849641). In summary, this variant is considered a hypomorphic allele and in combination with other variants in cis or trans, may result in reduced enzyme activity. Based on the above information this variant meets our laboratory’s criteria to be classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 09, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 38 of the PLG protein (p.Lys38Glu). This variant is present in population databases (rs73015965, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with plasminogen deficiency and ligneous conjunctivitis (PMID: 10233898, 15269832, 16849641, 23629776, 26340456, 27976734). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13583). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PLG protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 30, 2022	- -

Deep venous thrombosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

-

- -

Otitis media, susceptibility to Benign:1

Benign, no assertion criteria provided

research

Santos-Cortez Lab, University of Colorado School of Medicine

Jul 26, 2019

- -

Computational scores

Source: dbNSFP v4.3

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;D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.76	T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Uncertain	0.036	D
MutationAssessor	Uncertain	2.3	.;M;.
MutationTaster	Benign	4.9e-7	A;A
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Uncertain	0.64
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.017	D;T;D
Polyphen		0.88	.;P;.
Vest4		0.56
MVP		0.93
MPC		0.70
ClinPred		0.063	T
GERP RS		3.6
Varity_R		0.59
gMVP		0.61

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: rs73015965; hg19: chr6-161127501; COSMIC: COSV51987550;