8-42186171-T-G

Variant names:

• chr8-42186171-T-G
• rs63020761
• NM_000930.5:c.540-999A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000930.5(PLAT):​c.540-999A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000016 in 125,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000016 (0 hom., cov: 30)
• Consequence: PLAT NM_000930.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.21
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.12).

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.540-999A>C		intron	N/A	NP_000921.1	P00750-1
	PLAT	NM_033011.4		c.402-999A>C		intron	N/A	NP_127509.1	P00750-3
	PLAT	NM_001319189.2		c.364+1735A>C		intron	N/A	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.540-999A>C		intron	N/A	ENSP00000220809.4	P00750-1
	PLAT	ENST00000352041.7	TSL:1	c.402-999A>C		intron	N/A	ENSP00000270188.6	P00750-3
	PLAT	ENST00000521647.1	TSL:1	n.1986A>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0000160 AC: 2 AN: 125262 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000342

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.0000160 AC: 2 AN: 125262 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 60326

African (AFR) AF: 0.00 AC: 0 AN: 32464

American (AMR) AF: 0.00 AC: 0 AN: 12464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3110

East Asian (EAS) AF: 0.00 AC: 0 AN: 4298

South Asian (SAS) AF: 0.00 AC: 0 AN: 3900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7748

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.0000342 AC: 2 AN: 58506

Other (OTH) AF: 0.00 AC: 0 AN: 1712

Alfa AF: 0.00 Hom.: 15

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.082
DANN	Benign	0.16
PhyloP100		-3.2

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

dbSNP: rs63020761; hg19: chr8-42043689;