rs2227583

Positions:

• chr10-73915461-T-C
• chr10-73915461-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_002658.6(PLAU):​c.1119+62T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00829 in 1,488,076 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0078 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0083 (98 hom.)
• Consequence: PLAU NM_002658.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.558

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00778 (1185/152260) while in subpopulation SAS AF= 0.0237 (114/4810). AF 95% confidence interval is 0.0202. There are 16 homozygotes in gnomad4. There are 556 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1185 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLAU	NM_002658.6	c.1119+62T>C		intron_variant		ENST00000372764.4
C10orf55	NR_160938.1	n.268+1058A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLAU	ENST00000372764.4	c.1119+62T>C		intron_variant		1	NM_002658.6	P1
C10orf55	ENST00000409178.5	n.268+1058A>G		intron_variant, non_coding_transcript_variant		1
PLAU	ENST00000446342.5	c.1068+62T>C		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00782 AC: 1189 AN: 152142 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00786

Gnomad ASJ AF: 0.0181

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0239

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.00835 AC: 11152 AN: 1335816 Hom.: 98 AF XY: 0.00916 AC XY: 6033 AN XY: 658266

Gnomad4 AFR exome AF: 0.00150

Gnomad4 AMR exome AF: 0.00684

Gnomad4 ASJ exome AF: 0.0183

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0279

Gnomad4 FIN exome AF: 0.00681

Gnomad4 NFE exome AF: 0.00719

Gnomad4 OTH exome AF: 0.0107

GnomAD4 genome AF: 0.00778 AC: 1185 AN: 152260 Hom.: 16 Cov.: 32 AF XY: 0.00747 AC XY: 556 AN XY: 74446

Gnomad4 AFR AF: 0.00168

Gnomad4 AMR AF: 0.00778

Gnomad4 ASJ AF: 0.0181

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0237

Gnomad4 FIN AF: 0.00471

Gnomad4 NFE AF: 0.0107

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00588 Hom.: 4

Bravo AF: 0.00694

Asia WGS AF: 0.0100 AC: 37 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.7
DANN	Benign	0.76

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: rs2227583; hg19: chr10-75675219;