chr9-133422462-C-T

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.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

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)

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=0.0015433729).

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
ADAMTS13	NM_139027.6 link	c.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
ADAMTS13	ENST00000355699.7 link	c.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.:

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.:

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:

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

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

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.:

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:

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:

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

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

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:

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

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.38

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.064

T;.;.;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0025

LIST_S2

Benign

0.66

T;T;T;T

MetaRNN

Benign

0.0015

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.75

N;.;N;N

PhyloP100

-1.4

PrimateAI

Benign

0.27

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

GERP RS

-6.5

PromoterAI

-0.0079

Neutral

(source)

Varity_R

0.054

gMVP

0.39

Mutation Taster

=93/7

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