rs2227567

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002658.6(PLAU):c.691A>C(p.Lys231Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00978 in 1,613,688 control chromosomes in the GnomAD database, including 1,010 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 503 hom., cov: 33)

Exomes 𝑓: 0.0061 ( 507 hom. )

Consequence

PLAU
NM_002658.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.794

Variant links:

Genes affected

PLAU (HGNC:9052): (plasminogen activator, urokinase) This gene encodes a secreted serine protease that converts plasminogen to plasmin. The encoded preproprotein is proteolytically processed to generate A and B polypeptide chains. These chains associate via a single disulfide bond to form the catalytically inactive high molecular weight urokinase-type plasminogen activator (HMW-uPA). HMW-uPA can be further processed into the catalytically active low molecular weight urokinase-type plasminogen activator (LMW-uPA). This low molecular weight form does not bind to the urokinase-type plasminogen activator receptor. Mutations in this gene may be associated with Quebec platelet disorder and late-onset Alzheimer's disease. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

PLAU links:

C10orf55 (HGNC:31008): (chromosome 10 putative open reading frame 55) Enables identical protein binding activity. [provided by Alliance of Genome Resources, Apr 2022]

C10orf55 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001355797).

BP6

Variant 10-73913990-A-C is Benign according to our data. Variant chr10-73913990-A-C is described in ClinVar as [Benign]. Clinvar id is 300753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLAU	NM_002658.6 link	c.691A>C	p.Lys231Gln	missense_variant	Exon 8 of 11	ENST00000372764.4	NP_002649.2	P00749-1A0A024QZM9Q59GZ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PLAU	ENST00000372764.4 link	c.691A>C	p.Lys231Gln	missense_variant	Exon 8 of 11	1	NM_002658.6	ENSP00000361850.3	P00749-1
C10orf55	ENST00000409178.5 link	n.269-915T>G		intron_variant	Intron 2 of 4	1
PLAU	ENST00000446342.5 link	c.640A>C	p.Lys214Gln	missense_variant	Exon 7 of 10	2		ENSP00000388474.1	P00749-2E7ET40
PLAU	ENST00000494287.1 link	n.*237A>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0449

AC:

6834

AN:

152170

Hom.:

498

Cov.:

show subpopulations

Gnomad AFR

AF:

0.152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0196

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0273

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000573

Gnomad OTH

AF:

0.0215

GnomAD3 exomes

AF:

0.0149

AC:

3740

AN:

251332

Hom.:

232

AF XY:

0.0124

AC XY:

1681

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.158

Gnomad AMR exome

AF:

0.00755

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0260

Gnomad FIN exome

AF:

0.000554

Gnomad NFE exome

AF:

0.000431

Gnomad OTH exome

AF:

0.00701

GnomAD4 exome

AF:

0.00611

AC:

8928

AN:

1461400

Hom.:

507

Cov.:

AF XY:

0.00613

AC XY:

4458

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.157

Gnomad4 AMR exome

AF:

0.00850

Gnomad4 ASJ exome

AF:

0.00165

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0247

Gnomad4 FIN exome

AF:

0.000356

Gnomad4 NFE exome

AF:

0.000246

Gnomad4 OTH exome

AF:

0.0125

GnomAD4 genome

AF:

0.0450

AC:

6855

AN:

152288

Hom.:

503

Cov.:

AF XY:

0.0437

AC XY:

3255

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.153

Gnomad4 AMR

AF:

0.0195

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0269

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000573

Gnomad4 OTH

AF:

0.0213

Alfa

AF:

0.00427

Hom.:

Bravo

AF:

0.0516

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.149

AC:

657

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.0183

AC:

2217

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Quebec platelet disorder

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.22

DANN

Benign

0.52

DEOGEN2

Benign

0.19

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.45

T;.

MetaRNN

Benign

0.0014

T;T

MetaSVM

Benign

-0.98

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.24

N;N

REVEL

Benign

0.0060

Sift

Benign

0.40

T;T

Sift4G

Benign

0.61

T;T

Polyphen

0.0020

B;.

Vest4

0.071

MPC

0.30

ClinPred

0.0023

GERP RS

-5.3

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over