Genetic Variant PLAT:n.19T>C (chr8-42207691-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000677722.1(PLAT):n.19T>C 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 0.183 in 151,440 control chromosomes in the GnomAD database, including 5,696 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 0.18 ( 5694 hom., cov: 31)

Exomes 𝑓: 0.083 ( 2 hom. )

Consequence

PLAT
ENST00000677722.1 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.401

Publications

9 publications found

Variant links:

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

PLAT links:

ENSG00000305013 (HGNC:):

ENSG00000305013 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
PLAT	NM_000930.5 link	c.-224T>C	upstream_gene_variant	ENST00000220809.9	NP_000921.1	P00750-1
PLAT	NM_033011.4 link	c.-224T>C	upstream_gene_variant		NP_127509.1	P00750-3
PLAT	NM_001319189.2 link	c.-224T>C	upstream_gene_variant		NP_001306118.1	P00750B4DN26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLAT	ENST00000220809.9 link	c.-224T>C		upstream_gene_variant		1	NM_000930.5	ENSP00000220809.4		P00750-1

Frequencies

GnomAD3 genomes

AF:

0.182

AC:

27554

AN:

151238

Hom.:

5664

Cov.:

show subpopulations

Gnomad AFR

AF:

0.512

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0941

Gnomad ASJ

AF:

0.0422

Gnomad EAS

AF:

0.0117

Gnomad SAS

AF:

0.0821

Gnomad FIN

AF:

0.0290

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0573

Gnomad OTH

AF:

0.139

GnomAD4 exome

AF:

0.0833

AC:

AN:

Hom.:

Cov.:

AF XY:

0.130

AC XY:

AN XY:

show subpopulations

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

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0429

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000047), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.308

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.183

AC:

27636

AN:

151356

Hom.:

5694

Cov.:

AF XY:

0.176

AC XY:

13025

AN XY:

73952

show subpopulations

African (AFR)

AF:

0.513

AC:

21105

AN:

41178

American (AMR)

AF:

0.0940

AC:

1429

AN:

15208

Ashkenazi Jewish (ASJ)

AF:

0.0422

AC:

146

AN:

3462

East Asian (EAS)

AF:

0.0111

AC:

AN:

5130

South Asian (SAS)

AF:

0.0813

AC:

386

AN:

4748

European-Finnish (FIN)

AF:

0.0290

AC:

305

AN:

10532

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0573

AC:

3886

AN:

67788

Other (OTH)

AF:

0.137

AC:

289

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

789

1578

2367

3156

3945

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

242

484

726

968

1210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0992

Hom.:

5147

Bravo

AF:

0.200

Asia WGS

AF:

0.107

AC:

371

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Benign

0.71

PhyloP100

0.40

PromoterAI

0.076

Neutral

(source)

Mutation Taster

=298/2

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over