rs11575933
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BS1BS2_Supporting
The ENST00000355699.7(ADAMTS13):c.1423C>T(p.Pro475Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,596,632 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
ENST00000355699.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ADAMTS13 | NM_139027.6 | c.1423C>T | p.Pro475Ser | missense_variant | 12/29 | ENST00000355699.7 | NP_620596.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ADAMTS13 | ENST00000355699.7 | c.1423C>T | p.Pro475Ser | missense_variant | 12/29 | 1 | NM_139027.6 | ENSP00000347927 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00273 AC: 415AN: 152158Hom.: 2 Cov.: 31
GnomAD3 exomes AF: 0.00582 AC: 1262AN: 217024Hom.: 18 AF XY: 0.00505 AC XY: 596AN XY: 118046
GnomAD4 exome AF: 0.00241 AC: 3482AN: 1444356Hom.: 56 Cov.: 35 AF XY: 0.00235 AC XY: 1682AN XY: 716798
GnomAD4 genome AF: 0.00273 AC: 415AN: 152276Hom.: 2 Cov.: 31 AF XY: 0.00349 AC XY: 260AN XY: 74454
ClinVar
Submissions by phenotype
Upshaw-Schulman syndrome Pathogenic:1Benign:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 03, 2002 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not provided Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 21, 2021 | Often reported in the literature as a polymorphism with a suspected northeastern Asian origin of the variant (Nakagawa et al., 2016; Tso et al., 2020); Reported in a deceased female infant with diarrhea negative hemolytic uremic syndrome and ADAMTS13 activity that was 54% of normal levels (Choi et al., 2011); Published functional crystal structure studies demonstrate that the P475S mutant destabilizes the protein leading to reduced substrate affinity and moderately reduced catalytic efficiency of the ADAMTS13 enzyme (Akiyama et al., 2013); Published functional cell transfection studies demonstrate the P475S variant resulted in very low enzyme activity (Kokame et al., 2002); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in 2.024% (642/31714 alleles) individuals of Latino background and 1.524% (273/17908 alleles) individuals of East Asian background in the gnomAD dataset, including multiple unrelated homozygous individuals (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12195022, 23715102, 19847791, 18665921, 27497325, 23621748, 22768050, 12181489, 21676167, 18581589, 21488199, 29669506, 29304523, 32588586) - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at