rs387906343

Positions:

• chr9-133459038-C-CA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_139027.6(ADAMTS13):​c.3975dup​(p.Glu1326ArgfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000515 in 1,613,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: ADAMTS13 NM_139027.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -2.03

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0345 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-133459038-C-CA is Pathogenic according to our data. Variant chr9-133459038-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 5807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS13	NM_139027.6	c.3975dup	p.Glu1326ArgfsTer6	frameshift_variant	29/29	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.3975dup	p.Glu1326ArgfsTer6	frameshift_variant	29/29	1	NM_139027.6	ENSP00000347927	A2

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000680 AC: 17 AN: 250006 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135562

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: 0.000151

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000507 AC: 74 AN: 1460902 Hom.: 0 Cov.: 30 AF XY: 0.0000495 AC XY: 36 AN XY: 726730

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000381

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74320

Gnomad4 AFR AF: 0.00

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: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.0000680

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Upshaw-Schulman syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 27, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2021	The p.Glu1382ArgfsX6 variant in ADAMTS13 has been reported in the homozygous or compound heterozygous state in over 20 individuals with hereditary or congenital thrombotic thrombocytopenic purpura (cTTP; Kentouche 2002 PMID: 12434890, Pimanda 2004 PMID: 14512317, Hassenpflug 2018 PMID: 29554699; van Dorland 2019 PMID: 30792199). This variant represents the most common pathogenic variant associated with cTTP in European populations (van Dorland 2019 PMID: 30792199) and has been identified in 0.015% (19/128102) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). It has also been reported in ClinVar (Variation ID 5807). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1382 and leads to a premature termination codon 6 amino acids downstream. This alteration occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In vitro functional studies support that the truncation impacts protein secretion (Pimanda 2004 PMID: 14512317, Shang 2006 PMID: 16597588, Hassenpflug 2018 PMID: 29554699). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cTTP. ACMG/AMP criteria applied: PM3_VeryStrong, PVS1_Moderate, PS3_Supporting. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 07, 2023	For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Glu1382Argfs*6) in the ADAMTS13 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 46 amino acid(s) of the ADAMTS13 protein. This variant is present in population databases (rs781855393, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with thrombotic thrombocytopenic purpura (PMID: 12434890, 22529288, 23346910, 29554699, 30792199). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5807). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2024	Observed multiple times with another ADAMTS13 variant in unrelated patients with thrombotic thrombocytopenic purpura in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (PMID: 12434890, 22529288, 29554699); Frameshift variant predicted to result in abnormal protein length as the last 46 amino acids are replaced with 5 different amino acids, and other similar variants have been reported in HGMD; Published functional studies demonstrate a damaging effect: abnormal protein secretion and reduced enzyme activity (PMID: 29554699, 14512317, 18835837, 16597588); This variant is associated with the following publications: (PMID: 31589614, 34789164, 23346910, 26139087, 30792199, 29554699, 12393505, 16807643, 14512317, 16597588, 23700827, 18835837, 22529288, 12434890, 20118810) -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs387906343; hg19: chr9-136324160;