rs2227580

Variant names:

• chr10-73911598-G-T
• rs2227580
• NM_002658.6:c.43G>T

Your query was ambiguous. Multiple possible variants found:

• chr10-73911598-G-T
• chr10-73911598-G-A
• chr10-73911598-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001145031.3(PLAU):​c.-294G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0086 in 1,613,832 control chromosomes in the GnomAD database, including 139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0087 (123 hom.)
• Consequence: PLAU NM_001145031.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.995
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038291514).
• BP6: Variant 10-73911598-G-T is Benign according to our data. Variant chr10-73911598-G-T is described in ClinVar as Benign. ClinVar VariationId is 300740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00765 (1165/152338) while in subpopulation SAS AF = 0.0236 (114/4828). AF 95% confidence interval is 0.0201. There are 16 homozygotes in GnomAd4. There are 551 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1165 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145031.3. 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.43G>T	p.Val15Leu	missense	Exon 2 of 11	NP_002649.2	P00749-1
	PLAU	NM_001145031.3		c.-294G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 10	NP_001138503.2	P00749-2
	PLAU	NM_001319191.2		c.-188G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 10	NP_001306120.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLAU	ENST00000372764.4	TSL:1 MANE Select	c.43G>T	p.Val15Leu	missense	Exon 2 of 11	ENSP00000361850.3	P00749-1
	C10orf55	ENST00000409178.5	TSL:1	n.884C>A		non_coding_transcript_exon	Exon 5 of 5
	PLAU	ENST00000446342.5	TSL:2	c.-294G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 10	ENSP00000388474.1	P00749-2

Frequencies

GnomAD3 genomes AF: 0.00768 AC: 1169 AN: 152220 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00615

Gnomad ASJ AF: 0.0181

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0105 AC: 2609 AN: 249498 AF XY: 0.0120

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.00678

Gnomad ASJ exome AF: 0.0185

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00535

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.00870 AC: 12712 AN: 1461494 Hom.: 123 Cov.: 32 AF XY: 0.00968 AC XY: 7035 AN XY: 727022

African (AFR) AF: 0.00188 AC: 63 AN: 33478

American (AMR) AF: 0.00669 AC: 299 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 483 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0281 AC: 2420 AN: 86204

European-Finnish (FIN) AF: 0.00675 AC: 359 AN: 53148

Middle Eastern (MID) AF: 0.0501 AC: 289 AN: 5768

European-Non Finnish (NFE) AF: 0.00735 AC: 8168 AN: 1111964

Other (OTH) AF: 0.0104 AC: 631 AN: 60392

GnomAD4 genome AF: 0.00765 AC: 1165 AN: 152338 Hom.: 16 Cov.: 32 AF XY: 0.00740 AC XY: 551 AN XY: 74488

African (AFR) AF: 0.00185 AC: 77 AN: 41572

American (AMR) AF: 0.00608 AC: 93 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0181 AC: 63 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0236 AC: 114 AN: 4828

European-Finnish (FIN) AF: 0.00471 AC: 50 AN: 10620

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0107 AC: 725 AN: 68032

Other (OTH) AF: 0.0123 AC: 26 AN: 2116

Alfa AF: 0.00943 Hom.: 39

Bravo AF: 0.00659

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.0115 AC: 99

ExAC AF: 0.0110 AC: 1339

Asia WGS AF: 0.0100 AC: 37 AN: 3478

EpiCase AF: 0.0123

EpiControl AF: 0.0122

ClinVar

ClinVar submissions

Significance: Benign

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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.90
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.85	T
PhyloP100		0.99
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.10
Sift	Benign	0.32	T
Sift4G	Pathogenic	0.0	D
Vest4		0.051
MutPred		0.12		Loss of sheet (P = 0.0181)
MPC		0.28
ClinPred		0.0095	T
GERP RS		2.8
PromoterAI		-0.041	Neutral
gMVP		0.51
Mutation Taster		=98/2	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: rs2227580; hg19: chr10-75671356; COSMIC: COSV65641865; COSMIC: COSV65641865;