rs8178750

Variant names:

• chr8-42187353-G-A
• rs8178750
• ENST00000521647.1:n.804C>T

Variant summary

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

The ENST00000521647.1(PLAT):​n.804C>T variant causes a non coding transcript exon 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 ENST00000521647.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.758
• Publications: 10 publications found

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]

PLAT Gene-Disease associations (from GenCC):

• thrombophilia, familial, due to decreased release of tissue plasminogen activator

  Inheritance: AR, AD Classification: MODERATE, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen

ENSG00000304994 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PLAT	NM_000930.5	c.539+45C>T		intron_variant	Intron 6 of 13	ENST00000220809.9	NP_000921.1
PLAT	NM_033011.4	c.401+45C>T		intron_variant	Intron 5 of 12		NP_127509.1
PLAT	NM_001319189.2	c.364+553C>T		intron_variant	Intron 5 of 11		NP_001306118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLAT	ENST00000220809.9	c.539+45C>T		intron_variant	Intron 6 of 13	1	NM_000930.5	ENSP00000220809.4

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

GnomAD2 exomes AF: 0.145 AC: 27377 AN: 188338 AF XY: 0.145

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 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

African (AFR) AF: 0.228 AC: 7050 AN: 30946

American (AMR) AF: 0.0913 AC: 3278 AN: 35918

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 2935 AN: 20798

East Asian (EAS) AF: 0.0279 AC: 1071 AN: 38372

South Asian (SAS) AF: 0.127 AC: 9272 AN: 72764

European-Finnish (FIN) AF: 0.246 AC: 8882 AN: 36168

Middle Eastern (MID) AF: 0.105 AC: 558 AN: 5292

European-Non Finnish (NFE) AF: 0.162 AC: 167866 AN: 1038584

Other (OTH) AF: 0.161 AC: 8922 AN: 55360

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

African (AFR) AF: 0.222 AC: 9229 AN: 41528

American (AMR) AF: 0.120 AC: 1837 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 429 AN: 3472

East Asian (EAS) AF: 0.0348 AC: 180 AN: 5176

South Asian (SAS) AF: 0.123 AC: 592 AN: 4832

European-Finnish (FIN) AF: 0.249 AC: 2633 AN: 10588

Middle Eastern (MID) AF: 0.127 AC: 37 AN: 292

European-Non Finnish (NFE) AF: 0.163 AC: 11059 AN: 68006

Other (OTH) AF: 0.180 AC: 381 AN: 2114

Alfa AF: 0.167 Hom.: 860

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
PhyloP100		0.76
Mutation Taster		=100/0	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: rs8178750; hg19: chr8-42044871; COSMIC: COSV104373083;