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

Genomes: 𝑓 0.0027 ( 2 hom., cov: 31)
Exomes 𝑓: 0.0024 ( 56 hom. )

Consequence

ADAMTS13
ENST00000355699.7 missense

Scores

18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:4

Conservation

PhyloP100: 0.964
Variant links:
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 Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.036265075).
BP6
Variant 9-133436943-C-T is Benign according to our data. Variant chr9-133436943-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5814.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=2}.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00273 (415/152276) while in subpopulation EAS AF= 0.0224 (116/5180). AF 95% confidence interval is 0.0191. There are 2 homozygotes in gnomad4. There are 260 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ADAMTS13NM_139027.6 linkuse as main transcriptc.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
ADAMTS13ENST00000355699.7 linkuse as main transcriptc.1423C>T p.Pro475Ser missense_variant 12/291 NM_139027.6 ENSP00000347927 A2Q76LX8-2

Frequencies

GnomAD3 genomes
AF:
0.00273
AC:
415
AN:
152158
Hom.:
2
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00465
Gnomad ASJ
AF:
0.00979
Gnomad EAS
AF:
0.0223
Gnomad SAS
AF:
0.00104
Gnomad FIN
AF:
0.0122
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000720
Gnomad OTH
AF:
0.00288
GnomAD3 exomes
AF:
0.00582
AC:
1262
AN:
217024
Hom.:
18
AF XY:
0.00505
AC XY:
596
AN XY:
118046
show subpopulations
Gnomad AFR exome
AF:
0.0000749
Gnomad AMR exome
AF:
0.0204
Gnomad ASJ exome
AF:
0.0107
Gnomad EAS exome
AF:
0.0158
Gnomad SAS exome
AF:
0.00169
Gnomad FIN exome
AF:
0.00823
Gnomad NFE exome
AF:
0.000622
Gnomad OTH exome
AF:
0.00353
GnomAD4 exome
AF:
0.00241
AC:
3482
AN:
1444356
Hom.:
56
Cov.:
35
AF XY:
0.00235
AC XY:
1682
AN XY:
716798
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.0169
Gnomad4 ASJ exome
AF:
0.0107
Gnomad4 EAS exome
AF:
0.0377
Gnomad4 SAS exome
AF:
0.00149
Gnomad4 FIN exome
AF:
0.00689
Gnomad4 NFE exome
AF:
0.000404
Gnomad4 OTH exome
AF:
0.00169
GnomAD4 genome
AF:
0.00273
AC:
415
AN:
152276
Hom.:
2
Cov.:
31
AF XY:
0.00349
AC XY:
260
AN XY:
74454
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.00464
Gnomad4 ASJ
AF:
0.00979
Gnomad4 EAS
AF:
0.0224
Gnomad4 SAS
AF:
0.00104
Gnomad4 FIN
AF:
0.0122
Gnomad4 NFE
AF:
0.000720
Gnomad4 OTH
AF:
0.00285
Alfa
AF:
0.00144
Hom.:
0
Bravo
AF:
0.00261
ESP6500AA
AF:
0.000455
AC:
2
ESP6500EA
AF:
0.00105
AC:
9
ExAC
AF:
0.00424
AC:
509
Asia WGS
AF:
0.0100
AC:
36
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Upshaw-Schulman syndrome Pathogenic:1Benign:2
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 03, 2002- -
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
not provided Uncertain:1Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 21, 2021Often 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 submitterclinical testingPreventionGenetics, part of Exact Sciences-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.087
BayesDel_addAF
Benign
-0.50
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
14
DANN
Benign
0.38
DEOGEN2
Benign
0.068
T;T;.;.
Eigen
Benign
-0.68
Eigen_PC
Benign
-0.59
FATHMM_MKL
Benign
0.68
D
LIST_S2
Benign
0.64
T;T;T;T
MetaRNN
Benign
0.036
T;T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
1.6
L;.;L;.
MutationTaster
Benign
4.6e-8
A;A;A;A;A
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-0.58
N;.;N;N
REVEL
Benign
0.065
Sift
Benign
0.41
T;.;T;T
Sift4G
Benign
0.39
T;T;T;.
Polyphen
0.024
B;.;B;B
Vest4
0.19
MVP
0.81
MPC
0.34
ClinPred
0.0065
T
GERP RS
4.2
Varity_R
0.085
gMVP
0.50

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs11575933; hg19: chr9-136302063; COSMIC: COSV63023582; API