chr8-42179966-C-A

Position:

• chr8-42179966-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000930.5(PLAT):​c.1323G>T​(p.Trp441Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLAT NM_000930.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.27

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLAT	NM_000930.5	c.1323G>T	p.Trp441Cys	missense_variant	12/14	ENST00000220809.9	NP_000921.1
PLAT	NM_033011.4	c.1185G>T	p.Trp395Cys	missense_variant	11/13		NP_127509.1
PLAT	NM_001319189.2	c.1056G>T	p.Trp352Cys	missense_variant	10/12		NP_001306118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLAT	ENST00000220809.9	c.1323G>T	p.Trp441Cys	missense_variant	12/14	1	NM_000930.5	ENSP00000220809.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455948 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 723802

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Mar 31, 2024

The c.1323G>T (p.W441C) alteration is located in exon 12 (coding exon 11) of the PLAT gene. This alteration results from a G to T substitution at nucleotide position 1323, causing the tryptophan (W) at amino acid position 441 to be replaced by a cysteine (C). 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;D;.;.;D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.3	L;L;.;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.6	D;D;D;D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.015	D;D;D;D;T;T
Sift4G	Benign	0.15	T;T;T;T;T;T
Polyphen		1.0	D;D;D;.;D;D
Vest4		0.82
MutPred		0.74		Gain of disorder (P = 0.0101);Gain of disorder (P = 0.0101);.;.;.;.;
MVP		0.99
MPC		0.90
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.91
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-42037484;