8-42180036-C-A

Variant names:

• chr8-42180036-C-A
• rs753320550
• NM_000930.5:c.1253G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000930.5(PLAT):​c.1253G>T​(p.Arg418Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,608,492 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R418H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PLAT NM_000930.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.484
• 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

ENSG00000304994 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1253G>T	p.Arg418Leu	missense	Exon 12 of 14	NP_000921.1	P00750-1
	PLAT	NM_033011.4		c.1115G>T	p.Arg372Leu	missense	Exon 11 of 13	NP_127509.1	P00750-3
	PLAT	NM_001319189.2		c.986G>T	p.Arg329Leu	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.1253G>T	p.Arg418Leu	missense	Exon 12 of 14	ENSP00000220809.4	P00750-1
	PLAT	ENST00000352041.7	TSL:1	c.1115G>T	p.Arg372Leu	missense	Exon 11 of 13	ENSP00000270188.6	P00750-3
	PLAT	ENST00000679300.1		c.1253G>T	p.Arg418Leu	missense	Exon 12 of 15	ENSP00000503050.1	A0A7I2YQ93

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32

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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456168 Hom.: 0 Cov.: 32 AF XY: 0.00000415 AC XY: 3 AN XY: 723646

African (AFR) AF: 0.00 AC: 0 AN: 33364

American (AMR) AF: 0.00 AC: 0 AN: 44010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25962

East Asian (EAS) AF: 0.00 AC: 0 AN: 39518

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53154

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108598

Other (OTH) AF: 0.00 AC: 0 AN: 60114

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74484

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	11
DANN	Benign	0.56
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.14	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.73	N
PhyloP100		0.48
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.32
Sift	Benign	0.40	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.54		Loss of loop (P = 0.0603)
MVP		0.59
MPC		0.21
ClinPred		0.046	T
GERP RS		-6.9
Varity_R		0.26
gMVP		0.40
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.43		Position offset: -11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs753320550; hg19: chr8-42037554;