rs2227567

chr10-73913990-A-Cchr10-73913990-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002658.6(PLAU):c.691A>C(p.Lys231Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00978 in 1,613,688 control chromosomes in the GnomAD database, including 1,010 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.045 (503 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (507 hom.)
• Consequence: PLAU NM_002658.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.794

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001355797).
• BP6: Variant 10-73913990-A-C is Benign according to our data. Variant chr10-73913990-A-C is described in ClinVar as [Benign]. Clinvar id is 300753.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLAU	NM_002658.6	c.691A>C	p.Lys231Gln	missense_variant	8/11	ENST00000372764.4
C10orf55	NR_160938.1	n.269-915T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLAU	ENST00000372764.4	c.691A>C	p.Lys231Gln	missense_variant	8/11	1	NM_002658.6	P1
C10orf55	ENST00000409178.5	n.269-915T>G		intron_variant, non_coding_transcript_variant		1
PLAU	ENST00000446342.5	c.640A>C	p.Lys214Gln	missense_variant	7/10	2

Frequencies

GnomAD3 genomes AF: 0.0449 AC: 6834 AN: 152170 Hom.: 498 Cov.: 33

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0273

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.0215

GnomAD3 exomes AF: 0.0149 AC: 3740 AN: 251332 Hom.: 232 AF XY: 0.0124 AC XY: 1681 AN XY: 135858

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.00755

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0260

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.000431

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00611 AC: 8928 AN: 1461400 Hom.: 507 Cov.: 32 AF XY: 0.00613 AC XY: 4458 AN XY: 727026

Gnomad4 AFR exome AF: 0.157

Gnomad4 AMR exome AF: 0.00850

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0247

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.000246

Gnomad4 OTH exome AF: 0.0125

GnomAD4 genome AF: 0.0450 AC: 6855 AN: 152288 Hom.: 503 Cov.: 33 AF XY: 0.0437 AC XY: 3255 AN XY: 74478

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.0195

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0269

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.00427 Hom.: 65

Bravo AF: 0.0516

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.149 AC: 657

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.0183 AC: 2217

Asia WGS AF: 0.0220 AC: 76 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000533

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 13, 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
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	0.22
Dann	Benign	0.52
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.45	T;.
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.24	N;N
REVEL	Benign	0.0060
Sift	Benign	0.40	T;T
Sift4G	Benign	0.61	T;T
Polyphen		0.0020	B;.
Vest4		0.071
MPC		0.30
ClinPred		0.0023	T
GERP RS		-5.3
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2227567; hg19: chr10-75673748;