8-42179965-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000930.5(PLAT):c.1324A>G(p.Thr442Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,608,300 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: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
PLAT
NM_000930.5 missense
NM_000930.5 missense
Scores
4
8
6
Clinical Significance
Conservation
PhyloP100: 7.37
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.768
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLAT | NM_000930.5 | c.1324A>G | p.Thr442Ala | missense_variant | 12/14 | ENST00000220809.9 | |
PLAT | NM_033011.4 | c.1186A>G | p.Thr396Ala | missense_variant | 11/13 | ||
PLAT | NM_001319189.2 | c.1057A>G | p.Thr353Ala | missense_variant | 10/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLAT | ENST00000220809.9 | c.1324A>G | p.Thr442Ala | missense_variant | 12/14 | 1 | NM_000930.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000418 AC: 1AN: 239394Hom.: 0 AF XY: 0.00000772 AC XY: 1AN XY: 129602
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GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1455938Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 723822
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GnomAD4 genome ? AF: 0.00000656 AC: 1AN: 152362Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74502
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 03, 2024 | The c.1324A>G (p.T442A) alteration is located in exon 12 (coding exon 11) of the PLAT gene. This alteration results from a A to G substitution at nucleotide position 1324, causing the threonine (T) at amino acid position 442 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D;D;.;.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;N;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D
REVEL
Pathogenic
Sift
Benign
D;D;D;T;T;T
Sift4G
Benign
T;T;T;T;T;T
Polyphen
P;P;B;.;P;P
Vest4
MVP
MPC
0.58
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at