19-43652320-T-C

Variant names:

• chr19-43652320-T-C
• rs2302524
• NM_002659.4:c.659A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002659.4(PLAUR):​c.659A>G​(p.Lys220Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,613,684 control chromosomes in the GnomAD database, including 22,884 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K220Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.17 (2334 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20550 hom.)
• Consequence: PLAUR NM_002659.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.53
• Publications: 49 publications found

Genes affected

PLAUR (HGNC:9053): (plasminogen activator, urokinase receptor) This gene encodes the receptor for urokinase plasminogen activator and, given its role in localizing and promoting plasmin formation, likely influences many normal and pathological processes related to cell-surface plasminogen activation and localized degradation of the extracellular matrix. It binds both the proprotein and mature forms of urokinase plasminogen activator and permits the activation of the receptor-bound pro-enzyme by plasmin. The protein lacks transmembrane or cytoplasmic domains and may be anchored to the plasma membrane by a glycosyl-phosphatidylinositol (GPI) moiety following cleavage of the nascent polypeptide near its carboxy-terminus. However, a soluble protein is also produced in some cell types. Alternative splicing results in multiple transcript variants encoding different isoforms. The proprotein experiences several post-translational cleavage reactions that have not yet been fully defined. [provided by RefSeq, Jul 2008]

ENSG00000308028 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002575338).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLAUR	NM_002659.4	c.659A>G	p.Lys220Arg	missense_variant	Exon 6 of 7	ENST00000340093.8	NP_002650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLAUR	ENST00000340093.8	c.659A>G	p.Lys220Arg	missense_variant	Exon 6 of 7	1	NM_002659.4	ENSP00000339328.3

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25585 AN: 152024 Hom.: 2329 Cov.: 32

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.0756

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.166

GnomAD2 exomes AF: 0.163 AC: 41001 AN: 251454 AF XY: 0.159

Gnomad AFR exome AF: 0.197

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.0591

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.163

Gnomad OTH exome AF: 0.170

GnomAD4 exome AF: 0.164 AC: 240282 AN: 1461542 Hom.: 20550 Cov.: 32 AF XY: 0.163 AC XY: 118859 AN XY: 727102

African (AFR) AF: 0.202 AC: 6761 AN: 33470

American (AMR) AF: 0.256 AC: 11454 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2986 AN: 26134

East Asian (EAS) AF: 0.0872 AC: 3460 AN: 39694

South Asian (SAS) AF: 0.158 AC: 13645 AN: 86250

European-Finnish (FIN) AF: 0.106 AC: 5653 AN: 53408

Middle Eastern (MID) AF: 0.173 AC: 999 AN: 5764

European-Non Finnish (NFE) AF: 0.167 AC: 185781 AN: 1111722

Other (OTH) AF: 0.158 AC: 9543 AN: 60378

GnomAD4 genome AF: 0.168 AC: 25622 AN: 152142 Hom.: 2334 Cov.: 32 AF XY: 0.168 AC XY: 12504 AN XY: 74388

African (AFR) AF: 0.202 AC: 8381 AN: 41504

American (AMR) AF: 0.201 AC: 3075 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 396 AN: 3470

East Asian (EAS) AF: 0.0754 AC: 390 AN: 5174

South Asian (SAS) AF: 0.144 AC: 694 AN: 4820

European-Finnish (FIN) AF: 0.102 AC: 1078 AN: 10610

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11056 AN: 67976

Other (OTH) AF: 0.164 AC: 346 AN: 2112

Alfa AF: 0.166 Hom.: 9755

Bravo AF: 0.179

TwinsUK AF: 0.162 AC: 599

ALSPAC AF: 0.169 AC: 651

ESP6500AA AF: 0.197 AC: 870

ESP6500EA AF: 0.167 AC: 1432

ExAC AF: 0.163 AC: 19773

Asia WGS AF: 0.120 AC: 420 AN: 3478

EpiCase AF: 0.159

EpiControl AF: 0.161

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;T;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.020
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.78	T;T;T;T
MetaRNN	Benign	0.0026	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N;.;.
PhyloP100		3.5
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.79	N;N;N;.
REVEL	Benign	0.11
Sift	Benign	0.071	T;D;D;.
Sift4G	Uncertain	0.018	D;D;D;D
Polyphen		0.16	B;B;B;.
Vest4		0.13
MPC		0.12
ClinPred		0.017	T
GERP RS		4.5
Varity_R		0.35
gMVP		0.35
Mutation Taster		=96/4	polymorphism (auto)

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: rs2302524; hg19: chr19-44156472; COSMIC: COSV55389007; COSMIC: COSV55389007;