rs121918030

chr6-160716680-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 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).

• 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

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 Uncertain_significance. Variant got 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 id is 13577.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLG	NM_000301.5	c.704G>A	p.Arg235His	missense_variant	7/19	ENST00000308192.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLG	ENST00000308192.14	c.704G>A	p.Arg235His	missense_variant	7/19	1	NM_000301.5	P1
PLG	ENST00000418964.2	c.755G>A	p.Arg252His	missense_variant	7/19	4
PLG	ENST00000297289.9	c.50-5728G>A		intron_variant		5
PLG	ENST00000706906.1	c.704G>A	p.Arg235His	missense_variant, NMD_transcript_variant	7/19

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Plasminogen deficiency, type I Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 15, 1999

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	A
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

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