8-42176053-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_000930.5(PLAT):c.1629G>A(p.Pro543=) 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

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]

ACMG classification

Verdict is Benign. Variant got -7 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 id is 712061.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-5.87 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLAT	NM_000930.5	c.1629G>A	p.Pro543=	synonymous_variant	14/14	ENST00000220809.9
PLAT	NM_033011.4	c.1491G>A	p.Pro497=	synonymous_variant	13/13
PLAT	NM_001319189.2	c.1362G>A	p.Pro454=	synonymous_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLAT	ENST00000220809.9	c.1629G>A	p.Pro543=	synonymous_variant	14/14	1	NM_000930.5	P1

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

GnomAD3 exomes AF: 0.000868 AC: 218 AN: 251294 Hom.: 0 AF XY: 0.00102 AC XY: 139 AN XY: 135818

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 SAS exome AF: 0.00137

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

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00169

Gnomad4 FIN exome AF: 0.000618

Gnomad4 NFE exome AF: 0.00119

Gnomad4 OTH exome AF: 0.00113

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

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.000473

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

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.12
Dann	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs141151565; hg19: chr8-42033571; COSMIC: COSV51529041; COSMIC: COSV51529041;