9-133426236-C-T

Position:

chr9-133426236-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate

The NM_139027.6(ADAMTS13):c.577C>T(p.Arg193Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ADAMTS13
NM_139027.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 3.03

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:

ADAMTS13 (HGNC:):

ADAMTS13 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a domain Peptidase M12B (size 206) in uniprot entity ATS13_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_139027.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.93

PP5

Variant 9-133426236-C-T is Pathogenic according to our data. Variant chr9-133426236-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68823.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-133426236-C-T is described in UniProt as null. Variant chr9-133426236-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS13	NM_139027.6 linkuse as main transcript	c.577C>T	p.Arg193Trp	missense_variant	6/29	ENST00000355699.7	NP_620596.2	Q76LX8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7 linkuse as main transcript	c.577C>T	p.Arg193Trp	missense_variant	6/29	1	NM_139027.6	ENSP00000347927.2		Q76LX8-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250796

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135702

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461070

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726882

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

ADAMTS13-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2024

The ADAMTS13 c.577C>T variant is predicted to result in the amino acid substitution p.Arg193Trp. This variant has been reported in the compound heterozygous and homozygous state in multiple individuals with thrombotic thrombocytopenic purpura (Matsumoto et al. 2004. PubMed ID: 14563640; Supplemental Table S1, van Dorland et al. 2019. PubMed ID: 30792199; Dai et al. 2020. PubMed ID: 33014938). In addition, the p.Arg193Trp change has been demonstrated to abolish ADAMTS13 enzymatic activity (Matsumoto et al. 2004. PubMed ID: 14563640; Pozzi et al. 2011. PubMed ID: 21937160). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD . This variant is interpreted as likely pathogenic. -

Upshaw-Schulman syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GenePathDx, GenePath diagnostics

Jul 07, 2017

- -

not provided

Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;.;.;.

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.93

D;D;D;D

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.5

M;.;M;M

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.3

D;D;D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.027

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;.

Polyphen

1.0

D;.;D;D

Vest4

0.84

MutPred

0.86

Loss of methylation at R193 (P = 0.0342);Loss of methylation at R193 (P = 0.0342);Loss of methylation at R193 (P = 0.0342);Loss of methylation at R193 (P = 0.0342);

MVP

0.93

MPC

1.1

ClinPred

0.98

GERP RS

1.6

Varity_R

0.44

gMVP

0.85

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

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