NM_139027.6:c.3178C>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 8P and 2B. PP5_Very_StrongBP4BS2_Supporting

The NM_139027.6(ADAMTS13):c.3178C>T(p.Arg1060Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,608,810 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1060Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00085 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

ADAMTS13
NM_139027.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21O:1

Conservation

PhyloP100: 3.19

Publications

43 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: Likely_pathogenic. The variant received 6 ACMG points.

PP5

Variant 9-133454548-C-T is Pathogenic according to our data. Variant chr9-133454548-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 68815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.0662958). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAd4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.3178C>T	p.Arg1060Trp	missense	Exon 24 of 29	NP_620596.2
ADAMTS13	NM_139025.5		c.3178C>T	p.Arg1060Trp	missense	Exon 24 of 29	NP_620594.1
ADAMTS13	NM_139026.6		c.3085C>T	p.Arg1029Trp	missense	Exon 24 of 29	NP_620595.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADAMTS13	ENST00000355699.7	TSL:1 MANE Select	c.3178C>T	p.Arg1060Trp	missense	Exon 24 of 29	ENSP00000347927.2
ADAMTS13	ENST00000371929.7	TSL:1	c.3178C>T	p.Arg1060Trp	missense	Exon 24 of 29	ENSP00000360997.3
ADAMTS13	ENST00000356589.6	TSL:1	c.3085C>T	p.Arg1029Trp	missense	Exon 24 of 29	ENSP00000348997.2

Frequencies

GnomAD3 genomes

AF:

0.000854

AC:

130

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00135

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000828

AC:

203

AN:

245122

AF XY:

0.000922

show subpopulations

Gnomad AFR exome

AF:

0.000439

Gnomad AMR exome

AF:

0.000551

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000271

Gnomad NFE exome

AF:

0.00133

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.00112

AC:

1631

AN:

1456452

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

768

AN XY:

724836

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33470

American (AMR)

AF:

0.000448

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000742

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.000517

AC:

AN:

48334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00132

AC:

1472

AN:

1111866

Other (OTH)

AF:

0.000663

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

109

217

326

434

543

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

156

208

260

<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:

0.000853

AC:

130

AN:

152358

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

41584

American (AMR)

AF:

0.000784

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00135

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000954

Hom.:

Bravo

AF:

0.000865

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000924

AC:

112

EpiCase

AF:

0.000709

EpiControl

AF:

0.00160

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Upshaw-Schulman syndrome (13)

not provided (7)

ADAMTS13-related disorder (1)

Thrombotic thrombocytopenic purpura (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.86

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.066

MetaSVM

Uncertain

-0.019

MutationAssessor

Uncertain

2.9

PhyloP100

3.2

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-6.1

REVEL

Uncertain

0.42

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.41

MVP

0.90

MPC

1.1

ClinPred

0.095

GERP RS

3.2

Varity_R

0.12

gMVP

0.77

Mutation Taster

=1/99

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over