rs2227568

Variant names:

• chr10-73914121-C-T
• rs2227568
• NM_002658.6:c.822C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002658.6(PLAU):​c.822C>T​(p.Asn274Asn) 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:3
• Conservation: PhyloP100: -1.09
• Publications: 19 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 -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 VariationId 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 rank	MANE	Protein	UniProt
PLAU	NM_002658.6	c.822C>T	p.Asn274Asn	synonymous_variant	Exon 8 of 11	ENST00000372764.4	NP_002649.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLAU	ENST00000372764.4	c.822C>T	p.Asn274Asn	synonymous_variant	Exon 8 of 11	1	NM_002658.6	ENSP00000361850.3

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

GnomAD2 exomes AF: 0.166 AC: 41745 AN: 250806 AF XY: 0.174

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 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

African (AFR) AF: 0.0612 AC: 2047 AN: 33472

American (AMR) AF: 0.0956 AC: 4273 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 7039 AN: 26124

East Asian (EAS) AF: 0.321 AC: 12736 AN: 39680

South Asian (SAS) AF: 0.240 AC: 20733 AN: 86216

European-Finnish (FIN) AF: 0.152 AC: 8129 AN: 53306

Middle Eastern (MID) AF: 0.174 AC: 1000 AN: 5744

European-Non Finnish (NFE) AF: 0.150 AC: 166738 AN: 1111580

Other (OTH) AF: 0.166 AC: 9992 AN: 60364

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

African (AFR) AF: 0.0618 AC: 2567 AN: 41558

American (AMR) AF: 0.0899 AC: 1375 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 914 AN: 3472

East Asian (EAS) AF: 0.308 AC: 1591 AN: 5164

South Asian (SAS) AF: 0.231 AC: 1116 AN: 4824

European-Finnish (FIN) AF: 0.142 AC: 1511 AN: 10612

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10259 AN: 68008

Other (OTH) AF: 0.122 AC: 257 AN: 2114

Alfa AF: 0.147 Hom.: 2902

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Quebec platelet disorder Benign:1

Jan 12, 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	-0.43
CADD	Benign	0.19
DANN	Benign	0.90
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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