8-42186171-T-A

Variant names:

• chr8-42186171-T-A
• rs63020761
• ENST00000521647.1:n.1986A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000521647.1(PLAT):​n.1986A>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 0.025 in 125,352 control chromosomes in the GnomAD database, including 61 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 0.025 (61 hom., cov: 30)
  • Failed GnomAD Quality Control
• Consequence: PLAT ENST00000521647.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.21
• Publications: 3 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=-1.13).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.025 (3133/125352) while in subpopulation SAS AF = 0.0542 (211/3894). AF 95% confidence interval is 0.0482. There are 61 homozygotes in GnomAd4. There are 1596 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 61 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLAT	NM_000930.5	c.540-999A>T		intron_variant	Intron 6 of 13	ENST00000220809.9	NP_000921.1
PLAT	NM_033011.4	c.402-999A>T		intron_variant	Intron 5 of 12		NP_127509.1
PLAT	NM_001319189.2	c.364+1735A>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.540-999A>T		intron_variant	Intron 6 of 13	1	NM_000930.5	ENSP00000220809.4

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3136 AN: 125250 Hom.: 61 Cov.: 30

Gnomad AFR AF: 0.00539

Gnomad AMI AF: 0.0716

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.0172

Gnomad SAS AF: 0.0541

Gnomad FIN AF: 0.0464

Gnomad MID AF: 0.0504

Gnomad NFE AF: 0.0334

Gnomad OTH AF: 0.0175

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0250 AC: 3133 AN: 125352 Hom.: 61 Cov.: 30 AF XY: 0.0264 AC XY: 1596 AN XY: 60420

African (AFR) AF: 0.00541 AC: 176 AN: 32560

American (AMR) AF: 0.0176 AC: 220 AN: 12484

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 43 AN: 3108

East Asian (EAS) AF: 0.0170 AC: 73 AN: 4290

South Asian (SAS) AF: 0.0542 AC: 211 AN: 3894

European-Finnish (FIN) AF: 0.0464 AC: 359 AN: 7744

Middle Eastern (MID) AF: 0.0385 AC: 10 AN: 260

European-Non Finnish (NFE) AF: 0.0334 AC: 1955 AN: 58500

Other (OTH) AF: 0.0173 AC: 30 AN: 1730

Alfa AF: 0.0194 Hom.: 15

Bravo AF: 0.0169

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.091
DANN	Benign	0.063
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism

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: rs63020761; hg19: chr8-42043689;