rs41314453

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_139027.6(ADAMTS13):c.2195C>T(p.Ala732Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,613,072 control chromosomes in the GnomAD database, including 165 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0098 ( 11 hom., cov: 33)

Exomes 𝑓: 0.014 ( 154 hom. )

Consequence

ADAMTS13
NM_139027.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.750

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037906468).

BP6

Variant 9-133442704-C-T is Benign according to our data. Variant chr9-133442704-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 227176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133442704-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00981 (1494/152366) while in subpopulation NFE AF= 0.0157 (1068/68026). AF 95% confidence interval is 0.0149. There are 11 homozygotes in gnomad4. There are 740 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6 link	c.2195C>T	p.Ala732Val	missense_variant	Exon 18 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.2195C>T	p.Ala732Val	missense_variant	Exon 18 of 29	1	NM_139027.6	ENSP00000347927.2		Q76LX8-2

Frequencies

GnomAD3 genomes

AF:

0.00982

AC:

1495

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00285

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00719

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0146

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0157

Gnomad OTH

AF:

0.00909

GnomAD3 exomes

AF:

0.00984

AC:

2460

AN:

250056

Hom.:

AF XY:

0.0101

AC XY:

1368

AN XY:

135572

show subpopulations

Gnomad AFR exome

AF:

0.00230

Gnomad AMR exome

AF:

0.00527

Gnomad ASJ exome

AF:

0.00299

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00301

Gnomad FIN exome

AF:

0.0118

Gnomad NFE exome

AF:

0.0160

Gnomad OTH exome

AF:

0.00917

GnomAD4 exome

AF:

0.0141

AC:

20633

AN:

1460706

Hom.:

154

Cov.:

AF XY:

0.0137

AC XY:

9948

AN XY:

726664

show subpopulations

Gnomad4 AFR exome

AF:

0.00233

Gnomad4 AMR exome

AF:

0.00586

Gnomad4 ASJ exome

AF:

0.00260

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00310

Gnomad4 FIN exome

AF:

0.0110

Gnomad4 NFE exome

AF:

0.0168

Gnomad4 OTH exome

AF:

0.0109

GnomAD4 genome

AF:

0.00981

AC:

1494

AN:

152366

Hom.:

Cov.:

AF XY:

0.00993

AC XY:

740

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.00284

Gnomad4 AMR

AF:

0.00718

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.0146

Gnomad4 NFE

AF:

0.0157

Gnomad4 OTH

AF:

0.00900

Alfa

AF:

0.0116

Hom.:

Bravo

AF:

0.00916

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0158

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0136

AC:

117

ExAC

AF:

0.0101

AC:

1229

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0129

EpiControl

AF:

0.0164

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2025	ADAMTS13: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 02, 2025	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 25, 2015	p.Ala732Val in exon 18 of ADAMTS13: This variant is not expected to have clinica l significance because it has been identified 1.6% (1013/65004) of all chromosom es tested by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs41314453). While in vitro studies showed a decreased secretion of t he ADAMTS13 protein containing this variant, functional assays did not demonstra te decreased activity (Plaimauer 2006, Feng 2013). -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Mar 04, 2025	- -

Upshaw-Schulman syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 07, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.088

T;.;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.68

T;T;T

MetaRNN

Benign

0.0038

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

M;M;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.8

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.33

T;T;T

Sift4G

Benign

0.098

T;T;.

Polyphen

0.95

P;P;P

Vest4

0.087

MPC

0.36

ClinPred

0.0066

GERP RS

1.5

Varity_R

0.042

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over