8-42180023-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000930.5(PLAT):c.1266G>C(p.Glu422Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000373 in 1,610,232 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000038 (1 hom.)
• Consequence: PLAT NM_000930.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0800

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15492031).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLAT	NM_000930.5	c.1266G>C	p.Glu422Asp	missense_variant	12/14	ENST00000220809.9
PLAT	NM_033011.4	c.1128G>C	p.Glu376Asp	missense_variant	11/13
PLAT	NM_001319189.2	c.999G>C	p.Glu333Asp	missense_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLAT	ENST00000220809.9	c.1266G>C	p.Glu422Asp	missense_variant	12/14	1	NM_000930.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000574 AC: 14 AN: 243894 Hom.: 0 AF XY: 0.0000682 AC XY: 9 AN XY: 131980

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000399

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000377 AC: 55 AN: 1457870 Hom.: 1 Cov.: 32 AF XY: 0.0000442 AC XY: 32 AN XY: 724764

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000559

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152362 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74506

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.1266G>C (p.E422D) alteration is located in exon 12 (coding exon 11) of the PLAT gene. This alteration results from a G to C substitution at nucleotide position 1266, causing the glutamic acid (E) at amino acid position 422 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	10
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D;D;.;.;T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.71	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.47	N;N;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.11	T;T;T;T;T;T
Sift4G	Benign	0.34	T;T;T;T;T;T
Polyphen		0.011	B;B;B;.;B;B
Vest4		0.15
MutPred		0.58		Gain of phosphorylation at S417 (P = 0.1989);Gain of phosphorylation at S417 (P = 0.1989);.;.;.;.;
MVP		0.82
MPC		0.16
ClinPred		0.062	T
GERP RS		0.86
Varity_R		0.30
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs540586282; hg19: chr8-42037541;