9-133432645-C-T
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_139027.6(ADAMTS13):c.1045C>T(p.Arg349Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000321 in 1,559,654 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 Pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000028 ( 0 hom. )
Consequence
ADAMTS13
NM_139027.6 missense
NM_139027.6 missense
Scores
8
9
2
Clinical Significance
Conservation
PhyloP100: 5.17
Genes affected
ADAMTS13 (HGNC:1366): (ADAM metallopeptidase with thrombospondin type 1 motif 13) This gene encodes a member of a family of proteins containing several distinct regions, including a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. The enzyme encoded by this gene specifically cleaves von Willebrand Factor (vWF). Defects in this gene are associated with thrombotic thrombocytopenic purpura. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.969
PP5
Variant 9-133432645-C-T is Pathogenic according to our data. Variant chr9-133432645-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 68799.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-133432645-C-T is described in UniProt as null. Variant chr9-133432645-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADAMTS13 | NM_139027.6 | c.1045C>T | p.Arg349Cys | missense_variant | 9/29 | ENST00000355699.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADAMTS13 | ENST00000355699.7 | c.1045C>T | p.Arg349Cys | missense_variant | 9/29 | 1 | NM_139027.6 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152266Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000590 AC: 1AN: 169582Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 89630
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GnomAD4 exome AF: 0.00000284 AC: 4AN: 1407388Hom.: 0 Cov.: 31 AF XY: 0.00000288 AC XY: 2AN XY: 694772
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152266Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74378
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2022 | 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. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ADAMTS13 function (PMID: 29554699, 32365113). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ADAMTS13 protein function. ClinVar contains an entry for this variant (Variation ID: 68799). This missense change has been observed in individual(s) with thrombotic thrombocytopenic purpura (PMID: 19055667, 29554699). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 349 of the ADAMTS13 protein (p.Arg349Cys). - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
T;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M;.;M;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D;D
REVEL
Uncertain
Sift
Uncertain
D;.;D;D
Sift4G
Pathogenic
D;D;D;.
Polyphen
D;.;D;D
Vest4
MutPred
Gain of catalytic residue at L350 (P = 0.0464);.;Gain of catalytic residue at L350 (P = 0.0464);.;
MVP
MPC
ClinPred
D
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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