rs2020920

Variant names:

• chr8-42207476-T-C
• rs2020920
• NM_000930.5:c.-27+18A>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.-27+18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 152,290 control chromosomes in the GnomAD database, including 3,175 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 0.14 (3172 hom., cov: 32)
  • Exomes 𝑓: 0.094 (3 hom.)
• Consequence: PLAT NM_000930.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.51
• Publications: 4 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: AD, AR Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

ENSG00000305013 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000930.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLAT	NM_000930.5	MANE Select	c.-27+18A>G		intron	N/A	NP_000921.1	P00750-1
	PLAT	NM_033011.4		c.-27+18A>G		intron	N/A	NP_127509.1	P00750-3
	PLAT	NM_001319189.2		c.-27+18A>G		intron	N/A	NP_001306118.1	B4DN26

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLAT	ENST00000220809.9	TSL:1 MANE Select	c.-27+18A>G		intron	N/A	ENSP00000220809.4	P00750-1
	PLAT	ENST00000352041.7	TSL:1	c.-27+18A>G		intron	N/A	ENSP00000270188.6	P00750-3
	PLAT	ENST00000679300.1		c.-27+18A>G		intron	N/A	ENSP00000503050.1	A0A7I2YQ93

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20794 AN: 152076 Hom.: 3152 Cov.: 32

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0742

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.0193

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0492

Gnomad OTH AF: 0.103

GnomAD4 exome AF: 0.0938 AC: 9 AN: 96 Hom.: 3 Cov.: 0 AF XY: 0.0857 AC XY: 6 AN XY: 70

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

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0513 AC: 4 AN: 78

Other (OTH) AF: 0.400 AC: 4 AN: 10

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0628932), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.137 AC: 20861 AN: 152194 Hom.: 3172 Cov.: 32 AF XY: 0.131 AC XY: 9744 AN XY: 74430

African (AFR) AF: 0.379 AC: 15730 AN: 41480

American (AMR) AF: 0.0741 AC: 1133 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 95 AN: 3470

East Asian (EAS) AF: 0.00463 AC: 24 AN: 5182

South Asian (SAS) AF: 0.0180 AC: 87 AN: 4830

European-Finnish (FIN) AF: 0.0193 AC: 205 AN: 10612

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0492 AC: 3347 AN: 68010

Other (OTH) AF: 0.101 AC: 214 AN: 2114

Alfa AF: 0.114 Hom.: 577

Bravo AF: 0.151

Asia WGS AF: 0.0430 AC: 151 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.5
DANN	Benign	0.46
PhyloP100		-1.5
PromoterAI		0.031	Neutral
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: rs2020920; hg19: chr8-42064994;