10-73911227-C-G

Variant names:

• chr10-73911227-C-G
• rs538342269
• NM_002658.6:c.-32+9C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002658.6(PLAU):​c.-32+9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000343 in 390,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (0 hom.)
• Consequence: PLAU NM_002658.6 intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -3.33
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS2: High AC in GnomAd4 at 33 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002658.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLAU	NM_002658.6	MANE Select	c.-32+9C>G		intron	N/A	NP_002649.2	P00749-1
	PLAU	NM_001441154.1		c.-31-298C>G		intron	N/A	NP_001428083.1
	PLAU	NM_001441155.1		c.-31-298C>G		intron	N/A	NP_001428084.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLAU	ENST00000372764.4	TSL:1 MANE Select	c.-32+9C>G		intron	N/A	ENSP00000361850.3	P00749-1
	C10orf55	ENST00000409178.5	TSL:1	n.1255G>C		non_coding_transcript_exon	Exon 5 of 5
	PLAU	ENST00000935791.1		c.-32+225C>G		intron	N/A	ENSP00000605850.1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000424 AC: 101 AN: 238198 Hom.: 0 Cov.: 0 AF XY: 0.000504 AC XY: 64 AN XY: 127090

African (AFR) AF: 0.00 AC: 0 AN: 4602

American (AMR) AF: 0.000191 AC: 1 AN: 5244

Ashkenazi Jewish (ASJ) AF: 0.000142 AC: 1 AN: 7032

East Asian (EAS) AF: 0.00 AC: 0 AN: 12184

South Asian (SAS) AF: 0.00180 AC: 49 AN: 27230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17412

Middle Eastern (MID) AF: 0.00467 AC: 5 AN: 1070

European-Non Finnish (NFE) AF: 0.000235 AC: 35 AN: 149186

Other (OTH) AF: 0.000702 AC: 10 AN: 14238

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152268 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74448

African (AFR) AF: 0.0000481 AC: 2 AN: 41574

American (AMR) AF: 0.000196 AC: 3 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4832

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000234

Asia WGS AF: 0.000580 AC: 2 AN: 3460

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Quebec platelet disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.14
DANN	Benign	0.61
PhyloP100		-3.3
PromoterAI		0.0092	Neutral
Mutation Taster		=100/0	polymorphism

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: rs538342269; hg19: chr10-75670985;