rs2020921

Positions:

• chr8-42187447-G-A
• chr8-42187447-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000930.5(PLAT):​c.490C>T​(p.Arg164Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 1,603,474 control chromosomes in the GnomAD database, including 344 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.013 (15 hom., cov: 33)
  • Exomes 𝑓: 0.019 (329 hom.)
• Consequence: PLAT NM_000930.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.15

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053712428).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0127 (1942/152358) while in subpopulation NFE AF= 0.0217 (1477/68026). AF 95% confidence interval is 0.0208. There are 15 homozygotes in gnomad4. There are 861 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLAT	NM_000930.5	c.490C>T	p.Arg164Trp	missense_variant	6/14	ENST00000220809.9	NP_000921.1
PLAT	NM_033011.4	c.352C>T	p.Arg118Trp	missense_variant	5/13		NP_127509.1
PLAT	NM_001319189.2	c.364+459C>T		intron_variant			NP_001306118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLAT	ENST00000220809.9	c.490C>T	p.Arg164Trp	missense_variant	6/14	1	NM_000930.5	ENSP00000220809.4

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1942 AN: 152240 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.00408

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00863

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.00828

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.0122 AC: 2966 AN: 243878 Hom.: 22 AF XY: 0.0127 AC XY: 1682 AN XY: 132444

Gnomad AFR exome AF: 0.00359

Gnomad AMR exome AF: 0.00528

Gnomad ASJ exome AF: 0.00739

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00377

Gnomad FIN exome AF: 0.00806

Gnomad NFE exome AF: 0.0207

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.0193 AC: 27988 AN: 1451116 Hom.: 329 Cov.: 34 AF XY: 0.0189 AC XY: 13651 AN XY: 722126

Gnomad4 AFR exome AF: 0.00407

Gnomad4 AMR exome AF: 0.00574

Gnomad4 ASJ exome AF: 0.00682

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00456

Gnomad4 FIN exome AF: 0.00898

Gnomad4 NFE exome AF: 0.0230

Gnomad4 OTH exome AF: 0.0166

GnomAD4 genome AF: 0.0127 AC: 1942 AN: 152358 Hom.: 15 Cov.: 33 AF XY: 0.0116 AC XY: 861 AN XY: 74516

Gnomad4 AFR AF: 0.00406

Gnomad4 AMR AF: 0.00856

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00828

Gnomad4 NFE AF: 0.0217

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0242 Hom.: 875

Bravo AF: 0.0121

TwinsUK AF: 0.0229 AC: 85

ALSPAC AF: 0.0236 AC: 91

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.0222 AC: 191

ExAC AF: 0.0121 AC: 1464

Asia WGS AF: 0.00260 AC: 10 AN: 3478

EpiCase AF: 0.0216

EpiControl AF: 0.0211

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;T;.;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.83	.;T;T;T
MetaRNN	Benign	0.0054	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.1	M;M;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Benign	0.047
Sift	Benign	0.10	T;T;T;D
Sift4G	Uncertain	0.051	T;T;D;.
Polyphen		0.037	B;B;B;.
Vest4		0.13
MPC		0.24
ClinPred		0.044	T
GERP RS		1.9
Varity_R		0.27
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs2020921; hg19: chr8-42044965; COSMIC: COSV54274230; COSMIC: COSV54274230;