10-73911598-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_002658.6(PLAU):c.43G>T(p.Val15Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0086 in 1,613,832 control chromosomes in the GnomAD database, including 139 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0076 ( 16 hom., cov: 32)

Exomes 𝑓: 0.0087 ( 123 hom. )

Consequence

PLAU
NM_002658.6 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.995

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038291514).

BP6

Variant 10-73911598-G-T is Benign according to our data. Variant chr10-73911598-G-T is described in ClinVar as [Benign]. Clinvar id is 300740.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-73911598-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00765 (1165/152338) while in subpopulation SAS AF= 0.0236 (114/4828). AF 95% confidence interval is 0.0201. There are 16 homozygotes in gnomad4. There are 551 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd at 1169 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLAU	NM_002658.6 linkuse as main transcript	c.43G>T	p.Val15Leu	missense_variant	2/11	ENST00000372764.4
C10orf55	NR_160938.1 linkuse as main transcript	n.884C>A		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLAU	ENST00000372764.4 linkuse as main transcript	c.43G>T	p.Val15Leu	missense_variant	2/11	1	NM_002658.6	P1	P00749-1
C10orf55	ENST00000409178.5 linkuse as main transcript	n.884C>A		non_coding_transcript_exon_variant	5/5	1

Frequencies

GnomAD3 genomes

AF:

0.00768

AC:

1169

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00186

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00615

Gnomad ASJ

AF:

0.0181

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0238

Gnomad FIN

AF:

0.00471

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0105

AC:

2609

AN:

249498

Hom.:

AF XY:

0.0120

AC XY:

1616

AN XY:

135156

show subpopulations

Gnomad AFR exome

AF:

0.00130

Gnomad AMR exome

AF:

0.00678

Gnomad ASJ exome

AF:

0.0185

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0262

Gnomad FIN exome

AF:

0.00535

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.0121

GnomAD4 exome

AF:

0.00870

AC:

12712

AN:

1461494

Hom.:

123

Cov.:

AF XY:

0.00968

AC XY:

7035

AN XY:

727022

show subpopulations

Gnomad4 AFR exome

AF:

0.00188

Gnomad4 AMR exome

AF:

0.00669

Gnomad4 ASJ exome

AF:

0.0185

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0281

Gnomad4 FIN exome

AF:

0.00675

Gnomad4 NFE exome

AF:

0.00735

Gnomad4 OTH exome

AF:

0.0104

GnomAD4 genome

AF:

0.00765

AC:

1165

AN:

152338

Hom.:

Cov.:

AF XY:

0.00740

AC XY:

551

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00185

Gnomad4 AMR

AF:

0.00608

Gnomad4 ASJ

AF:

0.0181

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0236

Gnomad4 FIN

AF:

0.00471

Gnomad4 NFE

AF:

0.0107

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.00974

Hom.:

Bravo

AF:

0.00659

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.0115

AC:

ExAC

AF:

0.0110

AC:

1339

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.0123

EpiControl

AF:

0.0122

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Quebec platelet disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

0.11

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

Cadd

Benign

Dann

Benign

0.90

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.49

T;.

MetaRNN

Benign

0.0038

T;T

MetaSVM

Benign

-0.85

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.45

Sift4G

Pathogenic

0.0

D;T

Vest4

0.051

MutPred

0.12

Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);

MPC

0.28

ClinPred

0.0095

GERP RS

2.8

gMVP

0.51

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

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