NM_139027.6:c.3975dupA
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_139027.6(ADAMTS13):c.3975dupA(p.Glu1326ArgfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000515 in 1,613,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_139027.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000680 AC: 17AN: 250006Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135562
GnomAD4 exome AF: 0.0000507 AC: 74AN: 1460902Hom.: 0 Cov.: 30 AF XY: 0.0000495 AC XY: 36AN XY: 726730
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74320
ClinVar
Submissions by phenotype
Upshaw-Schulman syndrome Pathogenic:3
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The p.Glu1382ArgfsX6 variant in ADAMTS13 has been reported in the homozygous or compound heterozygous state in over 20 individuals with hereditary or congenital thrombotic thrombocytopenic purpura (cTTP; Kentouche 2002 PMID: 12434890, Pimanda 2004 PMID: 14512317, Hassenpflug 2018 PMID: 29554699; van Dorland 2019 PMID: 30792199). This variant represents the most common pathogenic variant associated with cTTP in European populations (van Dorland 2019 PMID: 30792199) and has been identified in 0.015% (19/128102) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). It has also been reported in ClinVar (Variation ID 5807). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1382 and leads to a premature termination codon 6 amino acids downstream. This alteration occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In vitro functional studies support that the truncation impacts protein secretion (Pimanda 2004 PMID: 14512317, Shang 2006 PMID: 16597588, Hassenpflug 2018 PMID: 29554699). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cTTP. ACMG/AMP criteria applied: PM3_VeryStrong, PVS1_Moderate, PS3_Supporting. -
not provided Pathogenic:2
This sequence change creates a premature translational stop signal (p.Glu1382Argfs*6) in the ADAMTS13 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 46 amino acid(s) of the ADAMTS13 protein. This variant is present in population databases (rs781855393, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with thrombotic thrombocytopenic purpura (PMID: 12434890, 22529288, 23346910, 29554699, 30792199). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5807). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Observed multiple times with another ADAMTS13 variant in unrelated patients with thrombotic thrombocytopenic purpura in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (PMID: 12434890, 22529288, 29554699); Frameshift variant predicted to result in abnormal protein length as the last 46 amino acids are replaced with 5 different amino acids, and other similar variants have been reported in HGMD; Published functional studies demonstrate a damaging effect: abnormal protein secretion and reduced enzyme activity (PMID: 29554699, 14512317, 18835837, 16597588); This variant is associated with the following publications: (PMID: 31589614, 34789164, 23346910, 26139087, 30792199, 29554699, 12393505, 16807643, 14512317, 16597588, 23700827, 18835837, 22529288, 12434890, 20118810) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at