9-133442447-A-T

Position:

• chr9-133442447-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_139027.6(ADAMTS13):​c.2017A>T​(p.Ile673Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,562 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 0.686

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a region_of_interest Spacer (size 129) in uniprot entity ATS13_HUMAN there are 5 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, 0.891
• PP5: Variant 9-133442447-A-T is Pathogenic according to our data. Variant chr9-133442447-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68809.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-133442447-A-T is described in UniProt as null. Variant chr9-133442447-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS13	NM_139027.6	c.2017A>T	p.Ile673Phe	missense_variant	17/29	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.2017A>T	p.Ile673Phe	missense_variant	17/29	1	NM_139027.6	ENSP00000347927.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251280 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135896

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461562 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727088

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: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Upshaw-Schulman syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Dec 04, 2018

The ADAMTS13 c.2017A>T (p.Ile673Phe) missense variant has been reported in a compound heterozygous state in two patients with thrombotic thrombocytopenia purpura who had less than three percent of normal ADAMTS13 enzyme activity in human plasma and in one reportedly healthy individual with low (below 47% of normal) ADAMTS13 enzyme activity, where zygosity information is not provided (Matsumoto et al. 2004; Kokame et al. 2011). This variant was absent from 96 controls and is not reported in the 1000 Genomes Project, the Exome Variant Server, or the Exome Aggregation Consortium. The p.Ile673Phe variant protein was shown to be produced in normal amounts, but expression analysis in HeLa cells demonstrated absent secretion from cells, as is normal for the wild type protein (Matsumoto et al. 2004). Based on the evidence, the p.Ile673Phe 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. -

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;.;.
Eigen	Benign	0.017
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.7	M;M;.
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0020	D;D;.
Polyphen		1.0	D;D;D
Vest4		0.47
MutPred		0.76		Gain of phosphorylation at Y677 (P = 0.1233);Gain of phosphorylation at Y677 (P = 0.1233);.;
MVP		0.90
MPC		1.3
ClinPred		0.91	D
GERP RS		1.6
Varity_R		0.14
gMVP		0.86

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

Other links and lift over

dbSNP: rs281875307; hg19: chr9-136307568;