chr8-42176143-C-T

Variant names:

• chr8-42176143-C-T
• rs13306824
• NM_000930.5:c.1539G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000930.5(PLAT):​c.1539G>A​(p.Ser513Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,612,996 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (27 hom.)
• Consequence: PLAT NM_000930.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.19
• 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: AD, AR Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 8-42176143-C-T is Benign according to our data. Variant chr8-42176143-C-T is described in ClinVar as Benign. ClinVar VariationId is 708039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00139 (212/152228) while in subpopulation EAS AF = 0.0319 (165/5174). AF 95% confidence interval is 0.0279. There are 4 homozygotes in GnomAd4. There are 106 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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.1539G>A	p.Ser513Ser	synonymous	Exon 14 of 14	NP_000921.1	P00750-1
	PLAT	NM_033011.4		c.1401G>A	p.Ser467Ser	synonymous	Exon 13 of 13	NP_127509.1	P00750-3
	PLAT	NM_001319189.2		c.1272G>A	p.Ser424Ser	synonymous	Exon 12 of 12	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.1539G>A	p.Ser513Ser	synonymous	Exon 14 of 14	ENSP00000220809.4	P00750-1
	PLAT	ENST00000352041.7	TSL:1	c.1401G>A	p.Ser467Ser	synonymous	Exon 13 of 13	ENSP00000270188.6	P00750-3
	PLAT	ENST00000679300.1		c.1602G>A	p.Ser534Ser	synonymous	Exon 15 of 15	ENSP00000503050.1	A0A7I2YQ93

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 212 AN: 152110 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0318

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00303 AC: 754 AN: 249102 AF XY: 0.00268

Gnomad AFR exome AF: 0.000685

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0373

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00119 AC: 1738 AN: 1460768 Hom.: 27 Cov.: 31 AF XY: 0.00114 AC XY: 831 AN XY: 726616

African (AFR) AF: 0.000120 AC: 4 AN: 33460

American (AMR) AF: 0.000270 AC: 12 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.0341 AC: 1352 AN: 39648

South Asian (SAS) AF: 0.00127 AC: 109 AN: 86130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111426

Other (OTH) AF: 0.00399 AC: 241 AN: 60358

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152228 Hom.: 4 Cov.: 33 AF XY: 0.00142 AC XY: 106 AN XY: 74430

African (AFR) AF: 0.000433 AC: 18 AN: 41542

American (AMR) AF: 0.00111 AC: 17 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0319 AC: 165 AN: 5174

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68010

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.00154

Asia WGS AF: 0.0180 AC: 64 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.50
DANN	Benign	0.82
PhyloP100		-1.2
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs13306824; hg19: chr8-42033661; COSMIC: COSV51530167; COSMIC: COSV51530167;