rs281875299
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_139027.6(ADAMTS13):c.1787C>T(p.Ala596Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000753 in 1,461,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_139027.6 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251126Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135838
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461632Hom.: 0 Cov.: 36 AF XY: 0.00000963 AC XY: 7AN XY: 727108
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1Other:1
ClinVar contains an entry for this variant (Variation ID: 68805). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 596 of the ADAMTS13 protein (p.Ala596Val). This variant is present in population databases (rs281875299, gnomAD 0.01%). This missense change has been observed in individual(s) with thrombotic thrombocytopenic purpura (PMID: 15009458, 22783805, 28678087, 30312976, 31064749, 32496441). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ADAMTS13 function (PMID: 17849048, 22783805). For these reasons, this variant has been classified as Pathogenic. -
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Thrombotic thrombocytopenic purpura Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at