chr9-133422462-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_139027.6(ADAMTS13):​c.19C>T​(p.Arg7Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,613,772 control chromosomes in the GnomAD database, including 11,180 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R7Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.093 ( 802 hom., cov: 32)
Exomes 𝑓: 0.11 ( 10378 hom. )

Consequence

ADAMTS13
NM_139027.6 missense

Scores

18

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.39

Publications

33 publications found
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]
ADAMTS13 Gene-Disease associations (from GenCC):
  • congenital thrombotic thrombocytopenic purpura
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0015433729).
BP6
Variant 9-133422462-C-T is Benign according to our data. Variant chr9-133422462-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADAMTS13NM_139027.6 linkc.19C>T p.Arg7Trp missense_variant Exon 1 of 29 ENST00000355699.7 NP_620596.2 Q76LX8-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADAMTS13ENST00000355699.7 linkc.19C>T p.Arg7Trp missense_variant Exon 1 of 29 1 NM_139027.6 ENSP00000347927.2 Q76LX8-2

Frequencies

GnomAD3 genomes
AF:
0.0928
AC:
14117
AN:
152150
Hom.:
802
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0482
Gnomad AMI
AF:
0.149
Gnomad AMR
AF:
0.0759
Gnomad ASJ
AF:
0.107
Gnomad EAS
AF:
0.00289
Gnomad SAS
AF:
0.0383
Gnomad FIN
AF:
0.127
Gnomad MID
AF:
0.0854
Gnomad NFE
AF:
0.128
Gnomad OTH
AF:
0.0910
GnomAD2 exomes
AF:
0.0906
AC:
22741
AN:
251060
AF XY:
0.0918
show subpopulations
Gnomad AFR exome
AF:
0.0454
Gnomad AMR exome
AF:
0.0513
Gnomad ASJ exome
AF:
0.103
Gnomad EAS exome
AF:
0.00217
Gnomad FIN exome
AF:
0.122
Gnomad NFE exome
AF:
0.129
Gnomad OTH exome
AF:
0.0996
GnomAD4 exome
AF:
0.113
AC:
165459
AN:
1461504
Hom.:
10378
Cov.:
32
AF XY:
0.111
AC XY:
80750
AN XY:
727092
show subpopulations
African (AFR)
AF:
0.0454
AC:
1520
AN:
33480
American (AMR)
AF:
0.0530
AC:
2369
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.0994
AC:
2597
AN:
26136
East Asian (EAS)
AF:
0.00237
AC:
94
AN:
39700
South Asian (SAS)
AF:
0.0429
AC:
3698
AN:
86258
European-Finnish (FIN)
AF:
0.121
AC:
6415
AN:
53112
Middle Eastern (MID)
AF:
0.0992
AC:
572
AN:
5764
European-Non Finnish (NFE)
AF:
0.128
AC:
142023
AN:
1111936
Other (OTH)
AF:
0.102
AC:
6171
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.481
Heterozygous variant carriers
0
7949
15899
23848
31798
39747
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
4940
9880
14820
19760
24700
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0928
AC:
14123
AN:
152268
Hom.:
802
Cov.:
32
AF XY:
0.0924
AC XY:
6881
AN XY:
74462
show subpopulations
African (AFR)
AF:
0.0483
AC:
2009
AN:
41570
American (AMR)
AF:
0.0759
AC:
1161
AN:
15298
Ashkenazi Jewish (ASJ)
AF:
0.107
AC:
372
AN:
3468
East Asian (EAS)
AF:
0.00290
AC:
15
AN:
5180
South Asian (SAS)
AF:
0.0384
AC:
185
AN:
4822
European-Finnish (FIN)
AF:
0.127
AC:
1347
AN:
10608
Middle Eastern (MID)
AF:
0.0850
AC:
25
AN:
294
European-Non Finnish (NFE)
AF:
0.128
AC:
8684
AN:
68006
Other (OTH)
AF:
0.0896
AC:
189
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.497
Heterozygous variant carriers
0
654
1308
1961
2615
3269
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
166
332
498
664
830
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.111
Hom.:
3921
Bravo
AF:
0.0882
TwinsUK
AF:
0.133
AC:
492
ALSPAC
AF:
0.139
AC:
534
ESP6500AA
AF:
0.0517
AC:
228
ESP6500EA
AF:
0.125
AC:
1071
ExAC
AF:
0.0938
AC:
11390
Asia WGS
AF:
0.0260
AC:
90
AN:
3478
EpiCase
AF:
0.125
EpiControl
AF:
0.125

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Nov 10, 2018
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 12614216, 16160007, 32531546) -

not specified Benign:1
-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Upshaw-Schulman syndrome Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Benign
-0.65
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
0.38
DANN
Benign
0.68
DEOGEN2
Benign
0.064
T;.;.;.
Eigen
Benign
-1.8
Eigen_PC
Benign
-1.9
FATHMM_MKL
Benign
0.0025
N
LIST_S2
Benign
0.66
T;T;T;T
MetaRNN
Benign
0.0015
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.75
N;.;N;N
PhyloP100
-1.4
PrimateAI
Benign
0.27
T
PROVEAN
Benign
0.48
N;N;N;N
REVEL
Benign
0.056
Sift
Benign
0.090
T;T;T;T
Sift4G
Benign
0.10
T;T;T;.
Polyphen
0.0
B;.;B;B
Vest4
0.054
MPC
0.35
ClinPred
0.00086
T
GERP RS
-6.5
PromoterAI
-0.0079
Neutral
Varity_R
0.054
gMVP
0.39
Mutation Taster
=93/7
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs34024143; hg19: chr9-136287582; COSMIC: COSV63020622; COSMIC: COSV63020622; API