8-42179966-C-A

Variant names:

• chr8-42179966-C-A
• NM_000930.5:c.1323G>T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 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

ENSG00000304994 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

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.1323G>T	p.Trp441Cys	missense	Exon 12 of 14	NP_000921.1	P00750-1
	PLAT	NM_033011.4		c.1185G>T	p.Trp395Cys	missense	Exon 11 of 13	NP_127509.1	P00750-3
	PLAT	NM_001319189.2		c.1056G>T	p.Trp352Cys	missense	Exon 10 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.1323G>T	p.Trp441Cys	missense	Exon 12 of 14	ENSP00000220809.4	P00750-1
	PLAT	ENST00000352041.7	TSL:1	c.1185G>T	p.Trp395Cys	missense	Exon 11 of 13	ENSP00000270188.6	P00750-3
	PLAT	ENST00000679300.1		c.1323G>T	p.Trp441Cys	missense	Exon 12 of 15	ENSP00000503050.1	A0A7I2YQ93

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

African (AFR) AF: 0.00 AC: 0 AN: 33370

American (AMR) AF: 0.00 AC: 0 AN: 44018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25936

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 85398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108966

Other (OTH) AF: 0.00 AC: 0 AN: 60094

GnomAD4 genome Cov.: 32

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	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.3	L
PhyloP100		7.3
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.015	D
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.82
MutPred		0.74		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
Mutation Taster		=0/100	disease causing

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

Other links and lift over

hg19: chr8-42037484;