10-73911536-A-G

Position:

• chr10-73911536-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002658.6(PLAU):​c.-20A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00299 in 1,610,280 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (6 hom.)
• Consequence: PLAU NM_002658.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0820

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-73911536-A-G is Benign according to our data. Variant chr10-73911536-A-G is described in ClinVar as [Benign]. Clinvar id is 300737.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 353 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLAU	NM_002658.6	c.-20A>G		5_prime_UTR_variant	2/11	ENST00000372764.4	NP_002649.2
C10orf55	NR_160938.1	n.946T>C		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLAU	ENST00000372764.4	c.-20A>G		5_prime_UTR_variant	2/11	1	NM_002658.6	ENSP00000361850	P1
C10orf55	ENST00000409178.5	n.946T>C		non_coding_transcript_exon_variant	5/5	1

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 353 AN: 152118 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00375

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00256 AC: 626 AN: 244560 Hom.: 2 AF XY: 0.00267 AC XY: 355 AN XY: 132826

Gnomad AFR exome AF: 0.000439

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00703

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000363

Gnomad FIN exome AF: 0.00103

Gnomad NFE exome AF: 0.00422

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00306 AC: 4465 AN: 1458044 Hom.: 6 Cov.: 32 AF XY: 0.00305 AC XY: 2216 AN XY: 725370

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00747

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000430

Gnomad4 FIN exome AF: 0.00105

Gnomad4 NFE exome AF: 0.00352

Gnomad4 OTH exome AF: 0.00300

GnomAD4 genome AF: 0.00232 AC: 353 AN: 152236 Hom.: 1 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74444

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00721

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00375

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00329 Hom.: 1

Bravo AF: 0.00235

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	-0.82
CADD	Benign	8.9
DANN	Benign	0.50

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: rs201591610; hg19: chr10-75671294;