19-43668036-T-G

Variant names:

• chr19-43668036-T-G
• rs344783
• NM_002659.4:c.56-345A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002659.4(PLAUR):​c.56-345A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000108 in 926,256 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 29)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: PLAUR NM_002659.4 intron
• Scores: Splicing: ADA: 0.0001889
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.538
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLAUR	NM_002659.4	c.56-345A>C		intron_variant	Intron 1 of 6	ENST00000340093.8	NP_002650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLAUR	ENST00000340093.8	c.56-345A>C		intron_variant	Intron 1 of 6	1	NM_002659.4	ENSP00000339328.3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000108 AC: 1 AN: 926256 Hom.: 0 Cov.: 35 AF XY: 0.00000230 AC XY: 1 AN XY: 434906

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 18946

American (AMR) AF: 0.00 AC: 0 AN: 5430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7646

East Asian (EAS) AF: 0.00 AC: 0 AN: 7888

South Asian (SAS) AF: 0.00 AC: 0 AN: 31182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3386

European-Non Finnish (NFE) AF: 0.00000123 AC: 1 AN: 814910

Other (OTH) AF: 0.00 AC: 0 AN: 32498

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.7
DANN	Benign	0.35
PhyloP100		-0.54
PromoterAI		0.11	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.020		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: rs344783; hg19: chr19-44172188;