rs2227566

Positions:

• chr10-73913973-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002658.6(PLAU):​c.681-7C>T variant causes a splice region, splice polypyrimidine tract, 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 (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.50 (19388 hom., cov: 32)
  • Exomes 𝑓: 0.52 (208728 hom.)
• Consequence: PLAU NM_002658.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005973
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.341

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]

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

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 3 / 10). 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 id is 300752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-73913973-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLAU	NM_002658.6	c.681-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000372764.4
C10orf55	NR_160938.1	n.269-898G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLAU	ENST00000372764.4	c.681-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002658.6	P1
C10orf55	ENST00000409178.5	n.269-898G>A		intron_variant, non_coding_transcript_variant		1
PLAU	ENST00000446342.5	c.630-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.496 AC: 75330 AN: 151952 Hom.: 19381 Cov.: 32

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

GnomAD3 exomes AF: 0.453 AC: 113615 AN: 251014 Hom.: 29051 AF XY: 0.457 AC XY: 62021 AN XY: 135660

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 SAS exome AF: 0.305

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.: 34 AF XY: 0.519 AC XY: 376794 AN XY: 725790

Gnomad4 AFR exome AF: 0.455

Gnomad4 AMR exome AF: 0.331

Gnomad4 ASJ exome AF: 0.579

Gnomad4 EAS exome AF: 0.108

Gnomad4 SAS exome AF: 0.310

Gnomad4 FIN exome AF: 0.466

Gnomad4 NFE exome AF: 0.566

Gnomad4 OTH exome AF: 0.516

GnomAD4 genome AF: 0.496 AC: 75363 AN: 152070 Hom.: 19388 Cov.: 32 AF XY: 0.488 AC XY: 36296 AN XY: 74316

Gnomad4 AFR AF: 0.457

Gnomad4 AMR AF: 0.459

Gnomad4 ASJ AF: 0.586

Gnomad4 EAS AF: 0.116

Gnomad4 SAS AF: 0.295

Gnomad4 FIN AF: 0.475

Gnomad4 NFE AF: 0.566

Gnomad4 OTH AF: 0.560

Alfa AF: 0.561 Hom.: 32305

Bravo AF: 0.495

Asia WGS AF: 0.215 AC: 748 AN: 3478

EpiCase AF: 0.586

EpiControl AF: 0.597

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Quebec platelet disorder Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.5
DANN	Benign	0.79
BranchPoint Hunter		3.0

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

LitVar

Other links and lift over

dbSNP: rs2227566; hg19: chr10-75673731; COSMIC: COSV65642067; COSMIC: COSV65642067;