19-43649096-T-C

Position:

• chr19-43649096-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002659.4(PLAUR):​c.802A>G​(p.Met268Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00432 in 1,614,122 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0044 (22 hom.)
• Consequence: PLAUR NM_002659.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.68

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022387892).
• BP6: Variant 19-43649096-T-C is Benign according to our data. Variant chr19-43649096-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 782626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-43649096-T-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLAUR	NM_002659.4	c.802A>G	p.Met268Val	missense_variant	7/7	ENST00000340093.8	NP_002650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLAUR	ENST00000340093.8	c.802A>G	p.Met268Val	missense_variant	7/7	1	NM_002659.4	ENSP00000339328.3

Frequencies

GnomAD3 genomes AF: 0.00359 AC: 547 AN: 152214 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00838

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00500

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00361 AC: 907 AN: 251160 Hom.: 5 AF XY: 0.00370 AC XY: 502 AN XY: 135804

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00468

Gnomad ASJ exome AF: 0.00804

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00189

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00484

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00439 AC: 6421 AN: 1461790 Hom.: 22 Cov.: 32 AF XY: 0.00434 AC XY: 3158 AN XY: 727190

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00514

Gnomad4 ASJ exome AF: 0.00884

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00167

Gnomad4 FIN exome AF: 0.000468

Gnomad4 NFE exome AF: 0.00492

Gnomad4 OTH exome AF: 0.00457

GnomAD4 genome AF: 0.00359 AC: 547 AN: 152332 Hom.: 2 Cov.: 31 AF XY: 0.00375 AC XY: 279 AN XY: 74494

Gnomad4 AFR AF: 0.000745

Gnomad4 AMR AF: 0.00836

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00500

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00492 Hom.: 3

Bravo AF: 0.00424

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00317 AC: 385

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00676

EpiControl AF: 0.00693

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	PLAUR: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.041	T;T;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.78	T;T;T
MetaRNN	Benign	0.022	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;L;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.2	.;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.019	.;D;D
Sift4G	Uncertain	0.025	D;D;D
Polyphen		0.35, 0.21	.;B;B
Vest4		0.31
MVP		0.45
MPC		0.44
ClinPred		0.012	T
GERP RS		3.1
Varity_R		0.23
gMVP		0.67

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: rs138492321; hg19: chr19-44153248;