chr9-133455322-G-A

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.3287G>A(p.Arg1096His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0057 in 1,607,056 control chromosomes in the GnomAD database, including 390 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 (★★).

Frequency

Genomes: 𝑓 0.011 ( 94 hom., cov: 33)

Exomes 𝑓: 0.0051 ( 296 hom. )

Consequence

ADAMTS13
NM_139027.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.159

Publications

11 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=0.0026655197).

BP6

Variant 9-133455322-G-A is Benign according to our data. Variant chr9-133455322-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0878 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139027.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADAMTS13	NM_139027.6	MANE Select	c.3287G>A	p.Arg1096His	missense	Exon 25 of 29	NP_620596.2
ADAMTS13	NM_139025.5		c.3287G>A	p.Arg1096His	missense	Exon 25 of 29	NP_620594.1
ADAMTS13	NM_139026.6		c.3194G>A	p.Arg1065His	missense	Exon 25 of 29	NP_620595.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADAMTS13	ENST00000355699.7	TSL:1 MANE Select	c.3287G>A	p.Arg1096His	missense	Exon 25 of 29	ENSP00000347927.2
ADAMTS13	ENST00000371929.7	TSL:1	c.3287G>A	p.Arg1096His	missense	Exon 25 of 29	ENSP00000360997.3
ADAMTS13	ENST00000356589.6	TSL:1	c.3194G>A	p.Arg1065His	missense	Exon 25 of 29	ENSP00000348997.2

Frequencies

GnomAD3 genomes

AF:

0.0113

AC:

1725

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00186

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0914

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00367

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00226

Gnomad OTH

AF:

0.0229

GnomAD2 exomes

AF:

0.0181

AC:

4444

AN:

245752

AF XY:

0.0136

show subpopulations

Gnomad AFR exome

AF:

0.00149

Gnomad AMR exome

AF:

0.114

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000382

Gnomad FIN exome

AF:

0.00523

Gnomad NFE exome

AF:

0.00224

Gnomad OTH exome

AF:

0.0155

GnomAD4 exome

AF:

0.00511

AC:

7427

AN:

1454748

Hom.:

296

Cov.:

AF XY:

0.00443

AC XY:

3209

AN XY:

724060

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

33476

American (AMR)

AF:

0.110

AC:

4915

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.000277

AC:

AN:

39694

South Asian (SAS)

AF:

0.00126

AC:

109

AN:

86248

European-Finnish (FIN)

AF:

0.00465

AC:

216

AN:

46414

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00161

AC:

1789

AN:

1111952

Other (OTH)

AF:

0.00558

AC:

337

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

532

1063

1595

2126

2658

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

130

260

390

520

650

<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:

0.0114

AC:

1732

AN:

152308

Hom.:

Cov.:

AF XY:

0.0134

AC XY:

996

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00185

AC:

AN:

41552

American (AMR)

AF:

0.0918

AC:

1405

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.000829

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00367

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00226

AC:

154

AN:

68024

Other (OTH)

AF:

0.0227

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

156

233

311

389

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:

0.00297

Hom.:

Bravo

AF:

0.0185

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.0127

AC:

1546

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.00196

EpiControl

AF:

0.00142

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Upshaw-Schulman syndrome (2)

ADAMTS13-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.0030

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.035

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.00087

LIST_S2

Benign

0.23

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.29

PhyloP100

0.16

PrimateAI

Benign

0.22

PROVEAN

Benign

1.3

REVEL

Uncertain

0.60

Sift

Benign

0.43

Sift4G

Benign

0.91

Polyphen

0.0010

Vest4

0.062

MPC

0.41

ClinPred

0.0024

GERP RS

-6.6

PromoterAI

-0.042

Neutral

(source)

Varity_R

0.033

gMVP

0.23

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over