rs8178750

Positions:

• chr8-42187353-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000220809.9(PLAT):​c.539+45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,486,430 control chromosomes in the GnomAD database, including 20,031 homozygotes. 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: 𝑓 0.17 (2569 hom., cov: 33)
  • Exomes 𝑓: 0.16 (17462 hom.)
• Consequence: PLAT ENST00000220809.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.758

Genes affected

PLAT (HGNC:9051): (plasminogen activator, tissue type) This gene encodes tissue-type plasminogen activator, a secreted serine protease that converts the proenzyme plasminogen to plasmin, a fibrinolytic enzyme. The encoded preproprotein is proteolytically processed by plasmin or trypsin to generate heavy and light chains. These chains associate via disulfide linkages to form the heterodimeric enzyme. This enzyme plays a role in cell migration and tissue remodeling. Increased enzymatic activity causes hyperfibrinolysis, which manifests as excessive bleeding, while decreased activity leads to hypofibrinolysis, which can result in thrombosis or embolism. Alternative splicing of this gene results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLAT	NM_000930.5	c.539+45C>T		intron_variant		ENST00000220809.9	NP_000921.1
PLAT	NM_001319189.2	c.364+553C>T		intron_variant			NP_001306118.1
PLAT	NM_033011.4	c.401+45C>T		intron_variant			NP_127509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLAT	ENST00000220809.9	c.539+45C>T		intron_variant		1	NM_000930.5	ENSP00000220809	P1

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26513 AN: 152110 Hom.: 2568 Cov.: 33

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.0347

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.183

GnomAD3 exomes AF: 0.145 AC: 27377 AN: 188338 Hom.: 2235 AF XY: 0.145 AC XY: 14727 AN XY: 101562

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.0850

Gnomad ASJ exome AF: 0.153

Gnomad EAS exome AF: 0.0322

Gnomad SAS exome AF: 0.139

Gnomad FIN exome AF: 0.260

Gnomad NFE exome AF: 0.161

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.157 AC: 209834 AN: 1334202 Hom.: 17462 Cov.: 22 AF XY: 0.156 AC XY: 102351 AN XY: 655178

Gnomad4 AFR exome AF: 0.228

Gnomad4 AMR exome AF: 0.0913

Gnomad4 ASJ exome AF: 0.141

Gnomad4 EAS exome AF: 0.0279

Gnomad4 SAS exome AF: 0.127

Gnomad4 FIN exome AF: 0.246

Gnomad4 NFE exome AF: 0.162

Gnomad4 OTH exome AF: 0.161

GnomAD4 genome AF: 0.174 AC: 26524 AN: 152228 Hom.: 2569 Cov.: 33 AF XY: 0.174 AC XY: 12961 AN XY: 74426

Gnomad4 AFR AF: 0.222

Gnomad4 AMR AF: 0.120

Gnomad4 ASJ AF: 0.124

Gnomad4 EAS AF: 0.0348

Gnomad4 SAS AF: 0.123

Gnomad4 FIN AF: 0.249

Gnomad4 NFE AF: 0.163

Gnomad4 OTH AF: 0.180

Alfa AF: 0.167 Hom.: 547

Bravo AF: 0.166

Asia WGS AF: 0.127 AC: 443 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.5
DANN	Benign	0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs8178750; hg19: chr8-42044871; COSMIC: COSV104373083; COSMIC: COSV104373083;