8-42176049-C-T

Variant names:

• chr8-42176049-C-T
• rs776112395
• NM_000930.5:c.1633G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_000930.5(PLAT):​c.1633G>A​(p.Val545Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,828 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: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: PLAT NM_000930.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.77
• Publications: 2 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: Uncertain_significance. The variant received 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

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.1633G>A	p.Val545Met	missense	Exon 14 of 14	NP_000921.1	P00750-1
	PLAT	NM_033011.4		c.1495G>A	p.Val499Met	missense	Exon 13 of 13	NP_127509.1	P00750-3
	PLAT	NM_001319189.2		c.1366G>A	p.Val456Met	missense	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.1633G>A	p.Val545Met	missense	Exon 14 of 14	ENSP00000220809.4	P00750-1
	PLAT	ENST00000352041.7	TSL:1	c.1495G>A	p.Val499Met	missense	Exon 13 of 13	ENSP00000270188.6	P00750-3
	PLAT	ENST00000679300.1		c.1696G>A	p.Val566Met	missense	Exon 15 of 15	ENSP00000503050.1	A0A7I2YQ93

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000597 AC: 15 AN: 251350 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461828 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000335 AC: 15 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111970

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000116 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Benign	0.16
Eigen_PC	Benign	-0.079
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		1.8
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.93		Loss of catalytic residue at V545 (P = 0.0892)
MVP		0.93
MPC		0.71
ClinPred		0.81	D
GERP RS		1.1
Varity_R		0.66
gMVP		0.87
Mutation Taster		=60/40	polymorphism

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

Other links and lift over

dbSNP: rs776112395; hg19: chr8-42033567;