rs2227568

Positions:

• chr10-73914121-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002658.6(PLAU):​c.822C>T​(p.Asn274=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,613,432 control chromosomes in the GnomAD database, including 21,791 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1608 hom., cov: 33)
  • Exomes 𝑓: 0.16 (20183 hom.)
• Consequence: PLAU NM_002658.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.09

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 10-73914121-C-T is Benign according to our data. Variant chr10-73914121-C-T is described in ClinVar as [Benign]. Clinvar id is 300756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLAU	NM_002658.6	c.822C>T	p.Asn274=	synonymous_variant	8/11	ENST00000372764.4
C10orf55	NR_160938.1	n.269-1046G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLAU	ENST00000372764.4	c.822C>T	p.Asn274=	synonymous_variant	8/11	1	NM_002658.6	P1
C10orf55	ENST00000409178.5	n.269-1046G>A		intron_variant, non_coding_transcript_variant		1
PLAU	ENST00000446342.5	c.771C>T	p.Asn257=	synonymous_variant	7/10	2

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19827 AN: 152132 Hom.: 1609 Cov.: 33

Gnomad AFR AF: 0.0619

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.0899

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.124

GnomAD3 exomes AF: 0.166 AC: 41745 AN: 250806 Hom.: 4082 AF XY: 0.174 AC XY: 23557 AN XY: 135602

Gnomad AFR exome AF: 0.0655

Gnomad AMR exome AF: 0.0969

Gnomad ASJ exome AF: 0.268

Gnomad EAS exome AF: 0.312

Gnomad SAS exome AF: 0.245

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.159 AC: 232687 AN: 1461182 Hom.: 20183 Cov.: 34 AF XY: 0.163 AC XY: 118366 AN XY: 726930

Gnomad4 AFR exome AF: 0.0612

Gnomad4 AMR exome AF: 0.0956

Gnomad4 ASJ exome AF: 0.269

Gnomad4 EAS exome AF: 0.321

Gnomad4 SAS exome AF: 0.240

Gnomad4 FIN exome AF: 0.152

Gnomad4 NFE exome AF: 0.150

Gnomad4 OTH exome AF: 0.166

GnomAD4 genome AF: 0.130 AC: 19826 AN: 152250 Hom.: 1608 Cov.: 33 AF XY: 0.130 AC XY: 9701 AN XY: 74442

Gnomad4 AFR AF: 0.0618

Gnomad4 AMR AF: 0.0899

Gnomad4 ASJ AF: 0.263

Gnomad4 EAS AF: 0.308

Gnomad4 SAS AF: 0.231

Gnomad4 FIN AF: 0.142

Gnomad4 NFE AF: 0.151

Gnomad4 OTH AF: 0.122

Alfa AF: 0.150 Hom.: 2187

Bravo AF: 0.125

Asia WGS AF: 0.242 AC: 843 AN: 3478

EpiCase AF: 0.153

EpiControl AF: 0.152

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

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
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.19
DANN	Benign	0.90

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

Other links and lift over

dbSNP: rs2227568; hg19: chr10-75673879; COSMIC: COSV65641301; COSMIC: COSV65641301;