rs4065

Variant names:

• chr10-73916706-C-T
• rs4065
• NM_002658.6:c.*141C>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.*141C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 701,926 control chromosomes in the GnomAD database, including 99,198 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (20132 hom., cov: 33)
  • Exomes 𝑓: 0.52 (79066 hom.)
• Consequence: PLAU NM_002658.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0110
• Publications: 38 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: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-73916706-C-T is Benign according to our data. Variant chr10-73916706-C-T is described in ClinVar as Benign. ClinVar VariationId is 300765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLAU	NM_002658.6	c.*141C>T		3_prime_UTR_variant	Exon 11 of 11	ENST00000372764.4	NP_002649.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLAU	ENST00000372764.4	c.*141C>T		3_prime_UTR_variant	Exon 11 of 11	1	NM_002658.6	ENSP00000361850.3

Frequencies

GnomAD3 genomes AF: 0.505 AC: 76748 AN: 151990 Hom.: 20128 Cov.: 33

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.502

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.604

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.578

Gnomad OTH AF: 0.579

GnomAD4 exome AF: 0.517 AC: 284423 AN: 549818 Hom.: 79066 Cov.: 7 AF XY: 0.511 AC XY: 145491 AN XY: 284984

African (AFR) AF: 0.472 AC: 6775 AN: 14366

American (AMR) AF: 0.398 AC: 7844 AN: 19694

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 8624 AN: 14390

East Asian (EAS) AF: 0.106 AC: 3329 AN: 31482

South Asian (SAS) AF: 0.337 AC: 16145 AN: 47882

European-Finnish (FIN) AF: 0.460 AC: 14003 AN: 30420

Middle Eastern (MID) AF: 0.674 AC: 1476 AN: 2190

European-Non Finnish (NFE) AF: 0.585 AC: 210674 AN: 360136

Other (OTH) AF: 0.532 AC: 15553 AN: 29258

GnomAD4 genome AF: 0.505 AC: 76778 AN: 152108 Hom.: 20132 Cov.: 33 AF XY: 0.497 AC XY: 36952 AN XY: 74336

African (AFR) AF: 0.464 AC: 19243 AN: 41494

American (AMR) AF: 0.469 AC: 7169 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 2097 AN: 3470

East Asian (EAS) AF: 0.119 AC: 615 AN: 5178

South Asian (SAS) AF: 0.317 AC: 1531 AN: 4826

European-Finnish (FIN) AF: 0.469 AC: 4956 AN: 10558

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.578 AC: 39308 AN: 67976

Other (OTH) AF: 0.574 AC: 1209 AN: 2108

Alfa AF: 0.568 Hom.: 30129

Bravo AF: 0.505

Asia WGS AF: 0.218 AC: 759 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 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:1

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	-0.88
CADD	Benign	6.0
DANN	Benign	0.59
PhyloP100		-0.011
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: rs4065; hg19: chr10-75676464;