9-133424410-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_139027.6(ADAMTS13):c.262G>A(p.Val88Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,586 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_139027.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152122Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250930Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135738
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461464Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2AN XY: 727026
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152122Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74298
ClinVar
Submissions by phenotype
not provided Uncertain:1Other:1
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 88 of the ADAMTS13 protein (p.Val88Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with thrombotic thrombocytopenic purpura (PMID: 14597993, 15800115, 30792199). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68812). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ADAMTS13 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ADAMTS13 function (PMID: 16453338, 17003922). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
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Upshaw-Schulman syndrome Pathogenic:1
The ADAMTS13 c.262G>A (p.Val88Met) missense variant has been reported in three studies in which it was identified in a compound heterozygous state with another missense variant in six individuals from two families with familial thrombotic thrombocytopenia purpura (Bestetti et al. 2003; Noris et al. 2005; Peyvandi et al. 2006). In each family, one of the compound heterozygotes was clinically asymptomatic with severely reduced protease activity (Bestetti et al. 2003; Noris et al. 2005). The p.Val88Met variant was absent from 200 control subjects and is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database despite being found in a region of good sequence coverage, suggesting that the variant is rare. All compound heterozygotes tested from the two families showed ADAMTS13 protease activity of less than 10% of normal levels (Bestetti et al. 2003; Noris et al. 2005). In two heterozygous individuals from a single family, the protease activity was observed to be 50% of normal (Noris et al. 2005). Payvandi et al. (2006) and Noris et al. (2005) also analyzed secretion and activity in HEK293 cells and found reduced levels of between 30% - 40% for secretion and 18% to 40% activity compared to normal. Based on the collective evidence, the p.Val88Met variant is classified as likely pathogenic for familial thrombotic thrombocytopenia purpura. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at