19-43652226-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002659.4(PLAUR):c.753C>T(p.His251=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00437 in 1,613,966 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (24 hom.)
• Consequence: PLAUR NM_002659.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0002980
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.04

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 19-43652226-G-A is Benign according to our data. Variant chr19-43652226-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 773084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.04 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLAUR	NM_002659.4	c.753C>T	p.His251=	splice_region_variant, synonymous_variant	6/7	ENST00000340093.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLAUR	ENST00000340093.8	c.753C>T	p.His251=	splice_region_variant, synonymous_variant	6/7	1	NM_002659.4	P1

Frequencies

GnomAD3 genomes AF: 0.00313 AC: 476 AN: 152156 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00532

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00367 AC: 922 AN: 251418 Hom.: 3 AF XY: 0.00401 AC XY: 545 AN XY: 135890

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00496

Gnomad FIN exome AF: 0.00291

Gnomad NFE exome AF: 0.00549

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00450 AC: 6580 AN: 1461692 Hom.: 24 Cov.: 31 AF XY: 0.00462 AC XY: 3356 AN XY: 727150

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.00493

Gnomad4 FIN exome AF: 0.00288

Gnomad4 NFE exome AF: 0.00512

Gnomad4 OTH exome AF: 0.00290

GnomAD4 genome AF: 0.00313 AC: 476 AN: 152274 Hom.: 4 Cov.: 32 AF XY: 0.00305 AC XY: 227 AN XY: 74460

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00532

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00483 Hom.: 5

Bravo AF: 0.00271

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00492

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Aug 28, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	PLAUR: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	0.039
Dann	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00030
dbscSNV1_RF	Benign	0.21
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: rs4251946; hg19: chr19-44156378; COSMIC: COSV99078091; COSMIC: COSV99078091;