rs2227562

Positions:

• chr10-73913203-G-A
• chr10-73913203-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002658.6(PLAU):​c.369-87G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,567,112 control chromosomes in the GnomAD database, including 21,148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1620 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19528 hom.)
• Consequence: PLAU NM_002658.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00500

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-73913203-G-A is Benign according to our data. Variant chr10-73913203-G-A is described in ClinVar as [Benign]. Clinvar id is 1295119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLAU	NM_002658.6	c.369-87G>A		intron_variant		ENST00000372764.4	NP_002649.2
C10orf55	NR_160938.1	n.269-128C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLAU	ENST00000372764.4	c.369-87G>A		intron_variant		1	NM_002658.6	ENSP00000361850	P1
C10orf55	ENST00000409178.5	n.269-128C>T		intron_variant, non_coding_transcript_variant		1
PLAU	ENST00000446342.5	c.318-87G>A		intron_variant		2		ENSP00000388474
PLAU	ENST00000494287.1	n.444-87G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20196 AN: 152040 Hom.: 1621 Cov.: 32

Gnomad AFR AF: 0.0709

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.0904

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.125

GnomAD4 exome AF: 0.159 AC: 224800 AN: 1414954 Hom.: 19528 Cov.: 24 AF XY: 0.162 AC XY: 114560 AN XY: 705158

Gnomad4 AFR exome AF: 0.0704

Gnomad4 AMR exome AF: 0.0944

Gnomad4 ASJ exome AF: 0.269

Gnomad4 EAS exome AF: 0.321

Gnomad4 SAS exome AF: 0.239

Gnomad4 FIN exome AF: 0.152

Gnomad4 NFE exome AF: 0.149

Gnomad4 OTH exome AF: 0.165

GnomAD4 genome AF: 0.133 AC: 20194 AN: 152158 Hom.: 1620 Cov.: 32 AF XY: 0.133 AC XY: 9884 AN XY: 74382

Gnomad4 AFR AF: 0.0707

Gnomad4 AMR AF: 0.0904

Gnomad4 ASJ AF: 0.263

Gnomad4 EAS AF: 0.308

Gnomad4 SAS AF: 0.232

Gnomad4 FIN AF: 0.143

Gnomad4 NFE AF: 0.151

Gnomad4 OTH AF: 0.123

Alfa AF: 0.150 Hom.: 2163

Bravo AF: 0.127

Asia WGS AF: 0.243 AC: 848 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.5
DANN	Benign	0.38

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: rs2227562; hg19: chr10-75672961; COSMIC: COSV65641915; COSMIC: COSV65641915;