10-73911538-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002658.6(PLAU):c.-18C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,610,580 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0088 (24 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (16 hom.)
• Consequence: PLAU NM_002658.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.289

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 10-73911538-C-A is Benign according to our data. Variant chr10-73911538-C-A is described in ClinVar as [Benign]. Clinvar id is 300738.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00882 (1343/152344) while in subpopulation AFR AF= 0.0301 (1249/41560). AF 95% confidence interval is 0.0287. There are 24 homozygotes in gnomad4. There are 618 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1342 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLAU	NM_002658.6	c.-18C>A		5_prime_UTR_variant	2/11	ENST00000372764.4
C10orf55	NR_160938.1	n.944G>T		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLAU	ENST00000372764.4	c.-18C>A		5_prime_UTR_variant	2/11	1	NM_002658.6	P1
C10orf55	ENST00000409178.5	n.944G>T		non_coding_transcript_exon_variant	5/5	1

Frequencies

GnomAD3 genomes AF: 0.00882 AC: 1342 AN: 152226 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00232 AC: 567 AN: 244558 Hom.: 6 AF XY: 0.00181 AC XY: 241 AN XY: 132862

Gnomad AFR exome AF: 0.0303

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000363

Gnomad OTH exome AF: 0.000993

GnomAD4 exome AF: 0.000854 AC: 1246 AN: 1458236 Hom.: 16 Cov.: 32 AF XY: 0.000728 AC XY: 528 AN XY: 725466

Gnomad4 AFR exome AF: 0.0280

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000540

Gnomad4 OTH exome AF: 0.00207

GnomAD4 genome AF: 0.00882 AC: 1343 AN: 152344 Hom.: 24 Cov.: 32 AF XY: 0.00829 AC XY: 618 AN XY: 74508

Gnomad4 AFR AF: 0.0301

Gnomad4 AMR AF: 0.00457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00308 Hom.: 2

Bravo AF: 0.0100

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.70
Cadd	Benign	7.4
Dann	Benign	0.72

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: rs2227555; hg19: chr10-75671296;