19-43665357-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002659.4(PLAUR):c.269A>G(p.Glu90Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E90K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: PLAUR NM_002659.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.35

Genes affected

PLAUR (HGNC:9053): (plasminogen activator, urokinase receptor) This gene encodes the receptor for urokinase plasminogen activator and, given its role in localizing and promoting plasmin formation, likely influences many normal and pathological processes related to cell-surface plasminogen activation and localized degradation of the extracellular matrix. It binds both the proprotein and mature forms of urokinase plasminogen activator and permits the activation of the receptor-bound pro-enzyme by plasmin. The protein lacks transmembrane or cytoplasmic domains and may be anchored to the plasma membrane by a glycosyl-phosphatidylinositol (GPI) moiety following cleavage of the nascent polypeptide near its carboxy-terminus. However, a soluble protein is also produced in some cell types. Alternative splicing results in multiple transcript variants encoding different isoforms. The proprotein experiences several post-translational cleavage reactions that have not yet been fully defined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLAUR	NM_002659.4	c.269A>G	p.Glu90Gly	missense_variant	3/7	ENST00000340093.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLAUR	ENST00000340093.8	c.269A>G	p.Glu90Gly	missense_variant	3/7	1	NM_002659.4	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.269A>G (p.E90G) alteration is located in exon 3 (coding exon 3) of the PLAUR gene. This alteration results from a A to G substitution at nucleotide position 269, causing the glutamic acid (E) at amino acid position 90 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	0.16
Eigen_PC	Benign	-0.019
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.78	T;T;T;T;T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.8	L;.;L;L;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-4.6	D;.;D;D;.;.;.
REVEL	Uncertain	0.49
Sift	Uncertain	0.0020	D;.;D;D;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;.;.
Polyphen		1.0	D;.;D;D;.;.;.
Vest4		0.65
MutPred		0.83		Gain of catalytic residue at V91 (P = 0.0446);Gain of catalytic residue at V91 (P = 0.0446);Gain of catalytic residue at V91 (P = 0.0446);Gain of catalytic residue at V91 (P = 0.0446);.;.;.;
MVP		0.64
MPC		0.40
ClinPred		0.96	D
GERP RS		3.8
Varity_R		0.68
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-44169509;