Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BS1BS2_Supporting

The NM_139027.6(ADAMTS13):c.1423C>T(p.Pro475Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,596,632 control chromosomes in the GnomAD database, including 58 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0024 ( 56 hom. )

Consequence

ADAMTS13
NM_139027.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:4

Conservation

PhyloP100: 0.964

Publications

37 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.036265075).

BP6

Variant 9-133436943-C-T is Benign according to our data. Variant chr9-133436943-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 5814.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00273 (415/152276) while in subpopulation EAS AF = 0.0224 (116/5180). AF 95% confidence interval is 0.0191. There are 2 homozygotes in GnomAd4. There are 260 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.1423C>T	p.Pro475Ser	missense	Exon 12 of 29	NP_620596.2
ADAMTS13	NM_139025.5		c.1423C>T	p.Pro475Ser	missense	Exon 12 of 29	NP_620594.1
ADAMTS13	NM_139026.6		c.1330C>T	p.Pro444Ser	missense	Exon 12 of 29	NP_620595.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADAMTS13	ENST00000355699.7	TSL:1 MANE Select	c.1423C>T	p.Pro475Ser	missense	Exon 12 of 29	ENSP00000347927.2
ADAMTS13	ENST00000371929.7	TSL:1	c.1423C>T	p.Pro475Ser	missense	Exon 12 of 29	ENSP00000360997.3
ADAMTS13	ENST00000356589.6	TSL:1	c.1330C>T	p.Pro444Ser	missense	Exon 12 of 29	ENSP00000348997.2

Frequencies

GnomAD3 genomes

AF:

0.00273

AC:

415

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00465

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.0223

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.00288

GnomAD2 exomes

AF:

0.00582

AC:

1262

AN:

217024

AF XY:

0.00505

show subpopulations

Gnomad AFR exome

AF:

0.0000749

Gnomad AMR exome

AF:

0.0204

Gnomad ASJ exome

AF:

0.0107

Gnomad EAS exome

AF:

0.0158

Gnomad FIN exome

AF:

0.00823

Gnomad NFE exome

AF:

0.000622

Gnomad OTH exome

AF:

0.00353

GnomAD4 exome

AF:

0.00241

AC:

3482

AN:

1444356

Hom.:

Cov.:

AF XY:

0.00235

AC XY:

1682

AN XY:

716798

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33380

American (AMR)

AF:

0.0169

AC:

704

AN:

41764

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

274

AN:

25696

East Asian (EAS)

AF:

0.0377

AC:

1475

AN:

39108

South Asian (SAS)

AF:

0.00149

AC:

124

AN:

83216

European-Finnish (FIN)

AF:

0.00689

AC:

349

AN:

50676

Middle Eastern (MID)

AF:

0.00124

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

0.000404

AC:

447

AN:

1105114

Other (OTH)

AF:

0.00169

AC:

101

AN:

59754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

185

371

556

742

927

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.00273

AC:

415

AN:

152276

Hom.:

Cov.:

AF XY:

0.00349

AC XY:

260

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41576

American (AMR)

AF:

0.00464

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00979

AC:

AN:

3472

East Asian (EAS)

AF:

0.0224

AC:

116

AN:

5180

South Asian (SAS)

AF:

0.00104

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0122

AC:

129

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000720

AC:

AN:

68020

Other (OTH)

AF:

0.00285

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00159

Hom.:

Bravo

AF:

0.00261

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00424

AC:

509

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Upshaw-Schulman syndrome (3)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.068

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.64

MetaRNN

Benign

0.036

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.6

PhyloP100

0.96

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.58

REVEL

Benign

0.065

Sift

Benign

0.41

Sift4G

Benign

0.39

Polyphen

0.024

Vest4

0.19

MVP

0.81

MPC

0.34

ClinPred

0.0065

GERP RS

4.2

Varity_R

0.085

gMVP

0.50

Mutation Taster

=83/17

polymorphism

(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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NM_139027.6:c.1423C>T

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