rs281875302

chr9-133424410-G-Achr9-133424410-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 7.42

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain Peptidase M12B (size 206) in uniprot entity ATS13_HUMAN there are 26 pathogenic changes around while only 4 benign (87%) 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, not_provided=1, Likely_pathogenic=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/exons	MANE	UniProt
ADAMTS13	NM_139027.6	c.262G>A	p.Val88Met	missense_variant	3/29	ENST00000355699.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.262G>A	p.Val88Met	missense_variant	3/29	1	NM_139027.6	A2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152122 Hom.: 0 Cov.: 32

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: 1 AN: 250930 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135738

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: 7 AN: 1461464 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727026

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: 2 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74298

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:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 14, 2022	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. Experimental studies have shown that this missense change affects ADAMTS13 function (PMID: 16453338, 17003922). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 68812). 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. 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 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). -

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	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.7	M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.39	T
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	D
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

Other links and lift over

dbSNP: rs281875302; hg19: chr9-136289530; COSMIC: COSV100747234;