8-42174613-T-C

Variant names:

• chr8-42174613-T-C
• rs4471024
• NM_000930.5:c.*1380A>G

Variant summary

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

The NM_000930.5(PLAT):​c.*1380A>G variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 151,732 control chromosomes in the GnomAD database, including 18,252 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 0.48 (18252 hom., cov: 30)
• Consequence: PLAT NM_000930.5 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.31
• Publications: 7 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLAT	NM_000930.5	c.*1380A>G		downstream_gene_variant		ENST00000220809.9	NP_000921.1
PLAT	NM_033011.4	c.*1380A>G		downstream_gene_variant			NP_127509.1
PLAT	NM_001319189.2	c.*1380A>G		downstream_gene_variant			NP_001306118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLAT	ENST00000220809.9	c.*1380A>G		downstream_gene_variant		1	NM_000930.5	ENSP00000220809.4

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73225 AN: 151614 Hom.: 18212 Cov.: 30

Gnomad AFR AF: 0.609

Gnomad AMI AF: 0.432

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.426

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.455

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

GnomAD4 genome AF: 0.483 AC: 73330 AN: 151732 Hom.: 18252 Cov.: 30 AF XY: 0.483 AC XY: 35778 AN XY: 74102

African (AFR) AF: 0.610 AC: 25192 AN: 41326

American (AMR) AF: 0.454 AC: 6923 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 1765 AN: 3466

East Asian (EAS) AF: 0.482 AC: 2480 AN: 5140

South Asian (SAS) AF: 0.431 AC: 2077 AN: 4814

European-Finnish (FIN) AF: 0.426 AC: 4483 AN: 10518

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.426 AC: 28905 AN: 67896

Other (OTH) AF: 0.461 AC: 971 AN: 2106

Alfa AF: 0.456 Hom.: 2540

Bravo AF: 0.490

Asia WGS AF: 0.483 AC: 1677 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.16
DANN	Benign	0.43
PhyloP100		-3.3

Splicing

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

Other links and lift over

dbSNP: rs4471024; hg19: chr8-42032131;