rs2227566

Variant names:

• chr10-73913973-C-T
• rs2227566
• NM_002658.6:c.681-7C>T

Variant summary

Our verdict is Benign. The variant received -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, 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

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

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLAU	NM_002658.6	c.681-7C>T		splice_region_variant, intron_variant	Intron 7 of 10	ENST00000372764.4	NP_002649.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLAU	ENST00000372764.4	c.681-7C>T		splice_region_variant, intron_variant	Intron 7 of 10	1	NM_002658.6	ENSP00000361850.3

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

GnomAD2 exomes AF: 0.453 AC: 113615 AN: 251014 AF XY: 0.457

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

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

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

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

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

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Quebec platelet disorder Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.5
DANN	Benign	0.79
PhyloP100		0.34
BranchPoint Hunter		3.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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