rs2227566

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002658.6(PLAU):c.681-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,610,644 control chromosomes in the GnomAD database, including 228,116 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 Benign (★★).

Frequency

Genomes: 𝑓 0.50 ( 19388 hom., cov: 32)

Exomes 𝑓: 0.52 ( 208728 hom. )

Consequence

PLAU
NM_002658.6 splice_region, intron

Scores

Splicing: ADA: 0.00005973

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.341

Publications

23 publications found

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 10-73913973-C-T is Benign according to our data. Variant chr10-73913973-C-T is described in ClinVar as Benign. ClinVar VariationId is 300752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002658.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PLAU	NM_002658.6	MANE Select	c.681-7C>T	splice_region intron	N/A	NP_002649.2	P00749-1
PLAU	NM_001441154.1		c.681-7C>T	splice_region intron	N/A	NP_001428083.1
PLAU	NM_001441155.1		c.681-7C>T	splice_region intron	N/A	NP_001428084.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PLAU	ENST00000372764.4	TSL:1 MANE Select	c.681-7C>T	splice_region intron	N/A	ENSP00000361850.3	P00749-1
C10orf55	ENST00000409178.5	TSL:1	n.269-898G>A	intron	N/A
PLAU	ENST00000894723.1		c.681-7C>T	splice_region intron	N/A	ENSP00000564782.1

Frequencies

GnomAD3 genomes

AF:

0.496

AC:

75330

AN:

151952

Hom.:

19381

Cov.:

show subpopulations

Gnomad AFR

AF:

0.457

Gnomad AMI

AF:

0.501

Gnomad AMR

AF:

0.460

Gnomad ASJ

AF:

0.586

Gnomad EAS

AF:

0.116

Gnomad SAS

AF:

0.295

Gnomad FIN

AF:

0.475

Gnomad MID

AF:

0.595

Gnomad NFE

AF:

0.566

Gnomad OTH

AF:

0.565

GnomAD2 exomes

AF:

0.453

AC:

113615

AN:

251014

AF XY:

0.457

show subpopulations

Gnomad AFR exome

AF:

0.454

Gnomad AMR exome

AF:

0.314

Gnomad ASJ exome

AF:

0.574

Gnomad EAS exome

AF:

0.102

Gnomad FIN exome

AF:

0.468

Gnomad NFE exome

AF:

0.574

Gnomad OTH exome

AF:

0.516

GnomAD4 exome

AF:

0.523

AC:

763207

AN:

1458574

Hom.:

208728

Cov.:

AF XY:

0.519

AC XY:

376794

AN XY:

725790

show subpopulations

African (AFR)

AF:

0.455

AC:

15205

AN:

33422

American (AMR)

AF:

0.331

AC:

14813

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.579

AC:

15114

AN:

26116

East Asian (EAS)

AF:

0.108

AC:

4279

AN:

39688

South Asian (SAS)

AF:

0.310

AC:

26683

AN:

86186

European-Finnish (FIN)

AF:

0.466

AC:

24878

AN:

53374

Middle Eastern (MID)

AF:

0.628

AC:

3621

AN:

5764

European-Non Finnish (NFE)

AF:

0.566

AC:

627487

AN:

1109014

Other (OTH)

AF:

0.516

AC:

31127

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

16933

33866

50798

67731

84664

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17020

34040

51060

68080

85100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.496

AC:

75363

AN:

152070

Hom.:

19388

Cov.:

AF XY:

0.488

AC XY:

36296

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.457

AC:

18952

AN:

41462

American (AMR)

AF:

0.459

AC:

7022

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.586

AC:

2034

AN:

3470

East Asian (EAS)

AF:

0.116

AC:

599

AN:

5182

South Asian (SAS)

AF:

0.295

AC:

1422

AN:

4820

European-Finnish (FIN)

AF:

0.475

AC:

5025

AN:

10574

Middle Eastern (MID)

AF:

0.592

AC:

174

AN:

294

European-Non Finnish (NFE)

AF:

0.566

AC:

38495

AN:

67962

Other (OTH)

AF:

0.560

AC:

1183

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1928

3857

5785

7714

9642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

652

1304

1956

2608

3260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.556

Hom.:

38897

Bravo

AF:

0.495

Asia WGS

AF:

0.215

AC:

748

AN:

3478

EpiCase

AF:

0.586

EpiControl

AF:

0.597

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Quebec platelet disorder (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

8.5

(source)

DANN

Benign

0.79

PhyloP100

0.34

BranchPoint Hunter

3.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000060

dbscSNV1_RF

Benign

0.0020

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over