rs28647808

Variant names:

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.1852C>G(p.Pro618Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0759 in 1,613,908 control chromosomes in the GnomAD database, including 5,313 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.058 ( 353 hom., cov: 32)

Exomes 𝑓: 0.078 ( 4960 hom. )

Consequence

ADAMTS13
NM_139027.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.56

Publications

46 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=0.0041890144).

BP6

Variant 9-133440409-C-G is Benign according to our data. Variant chr9-133440409-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0877 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6 link	c.1852C>G	p.Pro618Ala	missense_variant	Exon 16 of 29	ENST00000355699.7	NP_620596.2	Q76LX8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7 link	c.1852C>G	p.Pro618Ala	missense_variant	Exon 16 of 29	1	NM_139027.6	ENSP00000347927.2		Q76LX8-2

Frequencies

GnomAD3 genomes

AF:

0.0580

AC:

8825

AN:

152176

Hom.:

354

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0163

Gnomad AMI

AF:

0.0286

Gnomad AMR

AF:

0.0487

Gnomad ASJ

AF:

0.0760

Gnomad EAS

AF:

0.0199

Gnomad SAS

AF:

0.0228

Gnomad FIN

AF:

0.0617

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0896

Gnomad OTH

AF:

0.0630

GnomAD2 exomes

AF:

0.0605

AC:

15192

AN:

251016

AF XY:

0.0609

show subpopulations

Gnomad AFR exome

AF:

0.0153

Gnomad AMR exome

AF:

0.0327

Gnomad ASJ exome

AF:

0.0741

Gnomad EAS exome

AF:

0.0187

Gnomad FIN exome

AF:

0.0624

Gnomad NFE exome

AF:

0.0904

Gnomad OTH exome

AF:

0.0693

GnomAD4 exome

AF:

0.0778

AC:

113718

AN:

1461614

Hom.:

4960

Cov.:

AF XY:

0.0760

AC XY:

55271

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.0128

AC:

429

AN:

33476

American (AMR)

AF:

0.0341

AC:

1526

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0731

AC:

1910

AN:

26136

East Asian (EAS)

AF:

0.0232

AC:

923

AN:

39700

South Asian (SAS)

AF:

0.0225

AC:

1944

AN:

86258

European-Finnish (FIN)

AF:

0.0622

AC:

3306

AN:

53172

Middle Eastern (MID)

AF:

0.0602

AC:

347

AN:

5768

European-Non Finnish (NFE)

AF:

0.0891

AC:

99043

AN:

1111988

Other (OTH)

AF:

0.0710

AC:

4290

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

6308

12616

18925

25233

31541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3542

7084

10626

14168

17710

<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:

0.0579

AC:

8822

AN:

152294

Hom.:

353

Cov.:

AF XY:

0.0571

AC XY:

4254

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0162

AC:

675

AN:

41578

American (AMR)

AF:

0.0487

AC:

745

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0760

AC:

264

AN:

3472

East Asian (EAS)

AF:

0.0199

AC:

103

AN:

5172

South Asian (SAS)

AF:

0.0232

AC:

112

AN:

4826

European-Finnish (FIN)

AF:

0.0617

AC:

655

AN:

10618

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0896

AC:

6092

AN:

68010

Other (OTH)

AF:

0.0619

AC:

131

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

420

840

1261

1681

2101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

204

306

408

510

<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:

0.0805

Hom.:

432

Bravo

AF:

0.0556

TwinsUK

AF:

0.0928

AC:

344

ALSPAC

AF:

0.0955

AC:

368

ESP6500AA

AF:

0.0179

AC:

ESP6500EA

AF:

0.0863

AC:

742

ExAC

AF:

0.0629

AC:

7635

Asia WGS

AF:

0.0380

AC:

130

AN:

3478

EpiCase

AF:

0.0863

EpiControl

AF:

0.0878

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16160007, 26139087, 26284228, 28939980, 23733198, 32531546, 23847193, 22768050, 25934476, 12614216) -

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

0.31

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;T;.;.

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D;D;D

MetaRNN

Benign

0.0042

T;T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Pathogenic

2.9

M;.;M;.

PhyloP100

6.6

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-5.5

D;.;D;D

REVEL

Uncertain

0.30

Sift

Benign

0.050

D;.;D;T

Sift4G

Pathogenic

0.0

D;D;D;.

Polyphen

1.0

D;.;D;D

Vest4

0.59

MPC

0.64

ClinPred

0.010

GERP RS

5.1

Varity_R

0.27

gMVP

0.76

Mutation Taster

=80/20

polymorphism (auto)

(source)

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

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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