rs41314453

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_139027.6(ADAMTS13):c.2195C>T(p.Ala732Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,613,072 control chromosomes in the GnomAD database, including 165 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A732A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0098 ( 11 hom., cov: 33)

Exomes 𝑓: 0.014 ( 154 hom. )

Consequence

ADAMTS13
NM_139027.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.750

Publications

27 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)

ADAMTS13 links:

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=0.0037906468).

BP6

Variant 9-133442704-C-T is Benign according to our data. Variant chr9-133442704-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00981 (1494/152366) while in subpopulation NFE AF = 0.0157 (1068/68026). AF 95% confidence interval is 0.0149. There are 11 homozygotes in GnomAd4. There are 740 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6 link	c.2195C>T	p.Ala732Val	missense_variant	Exon 18 of 29	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7 link	c.2195C>T	p.Ala732Val	missense_variant	Exon 18 of 29	1	NM_139027.6	ENSP00000347927.2

Frequencies

GnomAD3 genomes

AF:

0.00982

AC:

1495

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00285

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00719

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0146

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0157

Gnomad OTH

AF:

0.00909

GnomAD2 exomes

AF:

0.00984

AC:

2460

AN:

250056

AF XY:

0.0101

show subpopulations

Gnomad AFR exome

AF:

0.00230

Gnomad AMR exome

AF:

0.00527

Gnomad ASJ exome

AF:

0.00299

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0118

Gnomad NFE exome

AF:

0.0160

Gnomad OTH exome

AF:

0.00917

GnomAD4 exome

AF:

0.0141

AC:

20633

AN:

1460706

Hom.:

154

Cov.:

AF XY:

0.0137

AC XY:

9948

AN XY:

726664

show subpopulations

African (AFR)

AF:

0.00233

AC:

AN:

33480

American (AMR)

AF:

0.00586

AC:

262

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00310

AC:

267

AN:

86254

European-Finnish (FIN)

AF:

0.0110

AC:

577

AN:

52320

Middle Eastern (MID)

AF:

0.00538

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0168

AC:

18689

AN:

1111966

Other (OTH)

AF:

0.0109

AC:

661

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

1383

2766

4148

5531

6914

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

708

1416

2124

2832

3540

<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:

0.00981

AC:

1494

AN:

152366

Hom.:

Cov.:

AF XY:

0.00993

AC XY:

740

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.00284

AC:

118

AN:

41586

American (AMR)

AF:

0.00718

AC:

110

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00269

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0146

AC:

155

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0157

AC:

1068

AN:

68026

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

163

245

326

408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0116

Hom.:

Bravo

AF:

0.00916

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0158

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0136

AC:

117

ExAC

AF:

0.0101

AC:

1229

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0129

EpiControl

AF:

0.0164

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ADAMTS13: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 25, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ala732Val in exon 18 of ADAMTS13: This variant is not expected to have clinica l significance because it has been identified 1.6% (1013/65004) of all chromosom es tested by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs41314453). While in vitro studies showed a decreased secretion of t he ADAMTS13 protein containing this variant, functional assays did not demonstra te decreased activity (Plaimauer 2006, Feng 2013). -

Upshaw-Schulman syndrome

Benign:1

Jan 07, 2022

Fulgent Genetics, Fulgent Genetics

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

0.11

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.088

T;.;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.68

T;T;T

MetaRNN

Benign

0.0038

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

M;M;.

PhyloP100

0.75

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.8

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.33

T;T;T

Sift4G

Benign

0.098

T;T;.

Polyphen

0.95

P;P;P

Vest4

0.087

MPC

0.36

ClinPred

0.0066

GERP RS

1.5

Varity_R

0.042

gMVP

0.34

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over