rs142572218

Variant names:

• chr9-133454548-C-T
• rs142572218
• NM_139027.6:c.3178C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-133454548-C-T
• chr9-133454548-C-A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 12P and 2B. PS3 PP5_Very_Strong BP4 BS2_Supporting

The NM_139027.6(ADAMTS13):​c.3178C>T​(p.Arg1060Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,608,810 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001780947: Published functional studies demonstrate intracellular retention (PMID:18031293, 29554699)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1060Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00085 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: 3.19
• Publications: 44 publications found

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 Gene-Disease associations (from GenCC):

• congenital thrombotic thrombocytopenic purpura

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001780947: Published functional studies demonstrate intracellular retention (PMID: 18031293, 29554699); SCV002143184: Experimental studies have shown that this missense change affects ADAMTS13 function (PMID: 18031293).; SCV006325085: Functional studies indicate that this sequence change significantly reduced enzyme activity and secretion (PMID: 18031293, 29554699).; SCV000916254: "In vitro analysis of the p. Arg1060Trp variant in HEK293T and Hela cells exhibited significantly reduced enzyme activity ranging from less than 5% to 11.4% of wild type enzyme activity (Schneppenheim et al. 2006; Tao et al. 2006; Camilleri et al. 2008; Lotta et al. 2012)."; SCV005047105: Functional in vitro studies show that this variant causes intracellular retention and impaired synthesis of ADAMTS13, indicating that this variant impacts protein function (Camilleri RS et al., PMID: 18031293; Tao Z et al., PMID: 16796708; Joly BS et al., PMID: 30312976, Donadelli et al., PMID: 17003922).; SCV005086775: Functional studies showed this variant causes severe intracellular retention (<5% secretion) of ADAMTS-13 (PMID: 18031293).; SCV005089670: Functional studies of the variant in mammalian cells demonstrated that this variant causes severe intracellular retention (<5% secretion) of the ADAMTS13 protein (PMID:18031293).; SCV002766528: Experimental evidence evaluating an impact on protein function demonstrated the variant results in reduced protein secretion and activity (e.g. Tao_2006, Camilleri_2008, Rurali_2015, Hassenpflug_2018, van Dorland_2019).; SCV004777659: Functional analysis showed that this variant had variable metalloprotease activity ranging from normal (Camilleri et al. 2009. PubMed ID: 18031293) to reduced function (~46% of wild type activity) (Rurali et al. 2015. PubMed ID: 26342041; Hassenpflug et al. 2018. PubMed ID: 29554699). Additional studies showed an increase in intracellular retention (Camilleri et al. 2009. PubMed ID: 18031293; Rurali et al. 2015. PubMed ID: 26342041; Hassenpflug et al. 2018. PubMed ID: 29554699).
• PP5: Variant 9-133454548-C-T is Pathogenic according to our data. Variant chr9-133454548-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 68815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0662958). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAd4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139027.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS13	NM_139027.6	MANE Select	c.3178C>T	p.Arg1060Trp	missense	Exon 24 of 29	NP_620596.2	Q76LX8-2
	ADAMTS13	NM_139025.5		c.3178C>T	p.Arg1060Trp	missense	Exon 24 of 29	NP_620594.1	Q76LX8-1
	ADAMTS13	NM_139026.6		c.3085C>T	p.Arg1029Trp	missense	Exon 24 of 29	NP_620595.1	Q76LX8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS13	ENST00000355699.7	TSL:1 MANE Select	c.3178C>T	p.Arg1060Trp	missense	Exon 24 of 29	ENSP00000347927.2	Q76LX8-2
	ADAMTS13	ENST00000371929.7	TSL:1	c.3178C>T	p.Arg1060Trp	missense	Exon 24 of 29	ENSP00000360997.3	Q76LX8-1
	ADAMTS13	ENST00000356589.6	TSL:1	c.3085C>T	p.Arg1029Trp	missense	Exon 24 of 29	ENSP00000348997.2	Q76LX8-3

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 130 AN: 152240 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00135

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000828 AC: 203 AN: 245122 AF XY: 0.000922

Gnomad AFR exome AF: 0.000439

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000271

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.00112 AC: 1631 AN: 1456452 Hom.: 1 Cov.: 32 AF XY: 0.00106 AC XY: 768 AN XY: 724836

African (AFR) AF: 0.000299 AC: 10 AN: 33470

American (AMR) AF: 0.000448 AC: 20 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000742 AC: 64 AN: 86230

European-Finnish (FIN) AF: 0.000517 AC: 25 AN: 48334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00132 AC: 1472 AN: 1111866

Other (OTH) AF: 0.000663 AC: 40 AN: 60342

GnomAD4 genome AF: 0.000853 AC: 130 AN: 152358 Hom.: 2 Cov.: 33 AF XY: 0.000631 AC XY: 47 AN XY: 74506

African (AFR) AF: 0.000529 AC: 22 AN: 41584

American (AMR) AF: 0.000784 AC: 12 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00135 AC: 92 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000954 Hom.: 0

Bravo AF: 0.000865

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000924 AC: 112

EpiCase AF: 0.000709

EpiControl AF: 0.00160

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
13	-	-	Upshaw-Schulman syndrome (13)
6	-	-	not provided (7)
1	-	-	ADAMTS13-related disorder (1)
1	-	-	Thrombotic thrombocytopenic purpura (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.066	T
MetaSVM	Uncertain	-0.019	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		3.2
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.41
MVP		0.90
MPC		1.1
ClinPred		0.095	T
GERP RS		3.2
Varity_R		0.12
gMVP		0.77
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs142572218; hg19: chr9-136319670; COSMIC: COSV63021054; COSMIC: COSV63021054;