chr8-42176053-C-T

Variant names:

• chr8-42176053-C-T
• rs141151565
• NM_000930.5:c.1629G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_000930.5(PLAT):​c.1629G>A​(p.Pro543Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,614,018 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00094 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: PLAT NM_000930.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.87
• Publications: 1 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 8-42176053-C-T is Benign according to our data. Variant chr8-42176053-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 712061.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-5.87 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.1629G>A	p.Pro543Pro	synonymous	Exon 14 of 14	NP_000921.1	P00750-1
	PLAT	NM_033011.4		c.1491G>A	p.Pro497Pro	synonymous	Exon 13 of 13	NP_127509.1	P00750-3
	PLAT	NM_001319189.2		c.1362G>A	p.Pro454Pro	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.1629G>A	p.Pro543Pro	synonymous	Exon 14 of 14	ENSP00000220809.4	P00750-1
	PLAT	ENST00000352041.7	TSL:1	c.1491G>A	p.Pro497Pro	synonymous	Exon 13 of 13	ENSP00000270188.6	P00750-3
	PLAT	ENST00000679300.1		c.1692G>A	p.Pro564Pro	synonymous	Exon 15 of 15	ENSP00000503050.1	A0A7I2YQ93

Frequencies

GnomAD3 genomes AF: 0.000940 AC: 143 AN: 152132 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000868 AC: 218 AN: 251294 AF XY: 0.00102

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.000637

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00100

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00114 AC: 1662 AN: 1461768 Hom.: 2 Cov.: 31 AF XY: 0.00113 AC XY: 820 AN XY: 727190

African (AFR) AF: 0.000807 AC: 27 AN: 33476

American (AMR) AF: 0.000559 AC: 25 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.00169 AC: 146 AN: 86254

European-Finnish (FIN) AF: 0.000618 AC: 33 AN: 53416

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00119 AC: 1323 AN: 1111918

Other (OTH) AF: 0.00113 AC: 68 AN: 60392

GnomAD4 genome AF: 0.000939 AC: 143 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.000847 AC XY: 63 AN XY: 74424

African (AFR) AF: 0.000626 AC: 26 AN: 41544

American (AMR) AF: 0.000392 AC: 6 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4822

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00143 AC: 97 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.000899

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00190

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.12
DANN	Benign	0.65
PhyloP100		-5.9
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs141151565; hg19: chr8-42033571; COSMIC: COSV51529041; COSMIC: COSV51529041;