9-133424410-G-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_139027.6(ADAMTS13):c.262G>A(p.Val88Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,586 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ADAMTS13
NM_139027.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.42

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 Likely_pathogenic. Variant got 9 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, 0.967

PP5

Variant 9-133424410-G-A is Pathogenic according to our data. Variant chr9-133424410-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68812.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1, not_provided=1}. Variant chr9-133424410-G-A is described in UniProt as null. Variant chr9-133424410-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6 link	c.262G>A	p.Val88Met	missense_variant	Exon 3 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.262G>A	p.Val88Met	missense_variant	Exon 3 of 29	1	NM_139027.6	ENSP00000347927.2		Q76LX8-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

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:

0.000478

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250930

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461464

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.0000302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 16, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 88 of the ADAMTS13 protein (p.Val88Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with thrombotic thrombocytopenic purpura (PMID: 14597993, 15800115, 30792199). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68812). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ADAMTS13 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ADAMTS13 function (PMID: 16453338, 17003922). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Upshaw-Schulman syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 05, 2019

The ADAMTS13 c.262G>A (p.Val88Met) missense variant has been reported in three studies in which it was identified in a compound heterozygous state with another missense variant in six individuals from two families with familial thrombotic thrombocytopenia purpura (Bestetti et al. 2003; Noris et al. 2005; Peyvandi et al. 2006). In each family, one of the compound heterozygotes was clinically asymptomatic with severely reduced protease activity (Bestetti et al. 2003; Noris et al. 2005). The p.Val88Met variant was absent from 200 control subjects and is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database despite being found in a region of good sequence coverage, suggesting that the variant is rare. All compound heterozygotes tested from the two families showed ADAMTS13 protease activity of less than 10% of normal levels (Bestetti et al. 2003; Noris et al. 2005). In two heterozygous individuals from a single family, the protease activity was observed to be 50% of normal (Noris et al. 2005). Payvandi et al. (2006) and Noris et al. (2005) also analyzed secretion and activity in HEK293 cells and found reduced levels of between 30% - 40% for secretion and 18% to 40% activity compared to normal. Based on the collective evidence, the p.Val88Met variant is classified as likely pathogenic for familial thrombotic thrombocytopenia purpura. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.;.;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Uncertain

0.71

MutationAssessor

Uncertain

2.7

M;.;M;M

PrimateAI

Benign

0.39

PROVEAN

Benign

-2.0

N;N;N;N

REVEL

Pathogenic

0.83

Sift

Uncertain

0.013

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;.

Polyphen

1.0

D;.;D;D

Vest4

0.56

MutPred

0.94

Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);

MVP

0.91

MPC

1.1

ClinPred

0.97

GERP RS

3.2

Varity_R

0.12

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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