8-42198531-C-G

Variant names:

• chr8-42198531-C-G
• rs2299609
• NM_000930.5:c.-26-5320G>C

Variant summary

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

The ENST00000220809.9(PLAT):​c.-26-5320G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 152,128 control chromosomes in the GnomAD database, including 23,936 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 0.55 (23936 hom., cov: 33)
• Consequence: PLAT ENST00000220809.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.349
• Publications: 8 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 (EAS) allele frequency at 95% confidence interval = 0.642 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000220809.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLAT	NM_000930.5	MANE Select	c.-26-5320G>C		intron	N/A	NP_000921.1
	PLAT	NM_033011.4		c.-26-5320G>C		intron	N/A	NP_127509.1
	PLAT	NM_001319189.2		c.-26-5320G>C		intron	N/A	NP_001306118.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLAT	ENST00000220809.9	TSL:1 MANE Select	c.-26-5320G>C		intron	N/A	ENSP00000220809.4
	PLAT	ENST00000352041.7	TSL:1	c.-26-5320G>C		intron	N/A	ENSP00000270188.6
	PLAT	ENST00000679300.1		c.-26-5320G>C		intron	N/A	ENSP00000503050.1

Frequencies

GnomAD3 genomes AF: 0.546 AC: 82978 AN: 152010 Hom.: 23922 Cov.: 33

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.572

Gnomad AMR AF: 0.652

Gnomad ASJ AF: 0.549

Gnomad EAS AF: 0.655

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.668

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.609

Gnomad OTH AF: 0.568

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.546 AC: 83013 AN: 152128 Hom.: 23936 Cov.: 33 AF XY: 0.553 AC XY: 41126 AN XY: 74370

African (AFR) AF: 0.343 AC: 14229 AN: 41494

American (AMR) AF: 0.653 AC: 9973 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 1907 AN: 3472

East Asian (EAS) AF: 0.656 AC: 3396 AN: 5176

South Asian (SAS) AF: 0.656 AC: 3170 AN: 4832

European-Finnish (FIN) AF: 0.668 AC: 7068 AN: 10578

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.609 AC: 41389 AN: 67984

Other (OTH) AF: 0.568 AC: 1199 AN: 2112

Alfa AF: 0.476 Hom.: 1560

Bravo AF: 0.535

Asia WGS AF: 0.617 AC: 2146 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.8
DANN	Benign	0.68
PhyloP100		-0.35
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: rs2299609; hg19: chr8-42056049; COSMIC: COSV54278422; COSMIC: COSV54278422;