rs121918030

Variant names:

• chr6-160716680-G-A
• rs121918030
• NM_000301.5:c.704G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP3_Strong PP5

The NM_000301.5(PLG):​c.704G>A​(p.Arg235His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R235C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: PLG NM_000301.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.92
• Publications: 10 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: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• angioedema, hereditary, 4

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 6-160716680-G-A is Pathogenic according to our data. Variant chr6-160716680-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 13577.Status of the report is no_assertion_criteria_provided, 0 stars.

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.704G>A	p.Arg235His	missense	Exon 7 of 19	NP_000292.1	P00747

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLG	ENST00000308192.14	TSL:1 MANE Select	c.704G>A	p.Arg235His	missense	Exon 7 of 19	ENSP00000308938.9	P00747
	PLG	ENST00000872438.1		c.704G>A	p.Arg235His	missense	Exon 7 of 21	ENSP00000542497.1
	PLG	ENST00000872435.1		c.704G>A	p.Arg235His	missense	Exon 7 of 19	ENSP00000542494.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460760 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726794

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111010

Other (OTH) AF: 0.00 AC: 0 AN: 60342

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Plasminogen deficiency, type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		9.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.97		Loss of MoRF binding (P = 0.007)
MVP		0.97
MPC		0.90
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.88
gMVP		0.90
Mutation Taster		=16/84	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

Other links and lift over

dbSNP: rs121918030; hg19: chr6-161137712; COSMIC: COSV51984776; COSMIC: COSV51984776;