rs36220240

Variant names:

• chr9-133436890-C-T
• rs36220240
• NM_139027.6:c.1370C>T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BS1_Supporting BS2

The NM_139027.6(ADAMTS13):​c.1370C>T​(p.Pro457Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00212 in 1,587,272 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0021 (9 hom.)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:6 B:1
• Conservation: PhyloP100: 4.64

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 Benign. Variant got -7 ACMG points.

• PM1: In a region_of_interest Cysteine-rich (size 116) in uniprot entity ATS13_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_139027.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.020557463).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00203 (308/152064) while in subpopulation AMR AF= 0.00439 (67/15254). AF 95% confidence interval is 0.00355. There are 1 homozygotes in gnomad4. There are 150 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6	c.1370C>T	p.Pro457Leu	missense_variant	Exon 12 of 29	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.1370C>T	p.Pro457Leu	missense_variant	Exon 12 of 29	1	NM_139027.6	ENSP00000347927.2

Frequencies

GnomAD3 genomes AF: 0.00203 AC: 308 AN: 151946 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00440

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00416

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00247

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00226 AC: 458 AN: 202740 Hom.: 1 AF XY: 0.00220 AC XY: 241 AN XY: 109764

Gnomad AFR exome AF: 0.000405

Gnomad AMR exome AF: 0.00163

Gnomad ASJ exome AF: 0.000110

Gnomad EAS exome AF: 0.0000641

Gnomad SAS exome AF: 0.000345

Gnomad FIN exome AF: 0.00593

Gnomad NFE exome AF: 0.00319

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00213 AC: 3055 AN: 1435208 Hom.: 9 Cov.: 35 AF XY: 0.00204 AC XY: 1454 AN XY: 711328

Gnomad4 AFR exome AF: 0.000572

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.0000391

Gnomad4 EAS exome AF: 0.0000258

Gnomad4 SAS exome AF: 0.000401

Gnomad4 FIN exome AF: 0.00524

Gnomad4 NFE exome AF: 0.00234

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00203 AC: 308 AN: 152064 Hom.: 1 Cov.: 31 AF XY: 0.00202 AC XY: 150 AN XY: 74340

Gnomad4 AFR AF: 0.000434

Gnomad4 AMR AF: 0.00439

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00416

Gnomad4 NFE AF: 0.00247

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00220 Hom.: 0

Bravo AF: 0.00176

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00247 AC: 21

ExAC AF: 0.00240 AC: 287

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:3

Nov 17, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ADAMTS13 c.1370C>T (p.Pro457Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 202740 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not comparable to an estimated frequency for a pathogenic variant in ADAMTS13 causing Thrombotic Thrombocytopenic Purpura allowing no conclusion about variant significance. c.1370C>T has been reported in the literature in at-least one compound heterozygous individual affected with Thrombotic Thrombocytopenic Purpura whose obligate carrier parents demonstrated 50% ADAMTS13 activity levels (example, Assink_2003, Manea_2007). It has also been reported as a single copy or an unspecified genotype in individuals with other unclear phenotypes such as congenital heart disease, acutely resolving episodes of TTP and in cohorts of individuals undergoing WES for rare bleeding disorders (example, Fidalgo_2017, Kateni_2017, Leinoe_2017). These data do not allow any firm conclusions about variant significance. This variant continues to be cited as a pathogenic variant associated with strong evidence for hereditary TTP (example, Hoon Rim_2020). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of ADAMTS13 activity although the primary data supporting this finding were not provided (example, Manea_2007). However, western blot analysis demonstrated a complete absence of ADAMTS13 using monoclonal and polyclonal antibodies against this protein. The following publications have been ascertained in the context of this evaluation (PMID: 12753286, 30046676, 32183147, 28866379, 28748566, 17187257, 23715102). Six clinical diagnostic laboratories have submitted conflicting clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; likely pathogenic, n=2; VUS, n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2 Benign:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with impaired secretion and reduced enzyme activity (Manea et al., 2007b; Katneni et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28866379, 21228398, 23346910, 17187257, 34426522, 28748566, 32183147, 32531546, 30046676, 17627784, 12753286) -

Oct 18, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, PS3_supporting -

Upshaw-Schulman syndrome Pathogenic:2

Mar 09, 2024

Institute of Immunology and Genetics Kaiserslautern

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PS3, PM1, PM3, PP5; Variant was found in heterozygous state -

Sep 05, 2017

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ADAMTS13 c.1370C>T (p.Pro457Leu) variant has been reported in at least two studies in which it is found in a compound heterozygous state in two individuals with familial thrombotic thrombocytopenia purpura and in a heterozygous state in an unaffected parent of each individual (Assink et al. 2003; Manea et al. 2007a). The p.Pro457Leu variant was absent from 50 control samples (Assink et al. 2003), but is reported at a frequency of 0.005899 in the European (Finnish) population of the Genome Aggregation Database with one homozygote present in the European (non-Finnish) population. One of the affected individuals was shown to have less than 5% enzyme activity compared to 50% activity seen in the unaffected parent, and in vitro studies showed impaired secretion and very low activity of the secreted variant proteins (Manea et al. 2007a; Manea et al. 2007b). Based on the evidence, the p.Pro457Leu 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. -

Atypical hemolytic-uremic syndrome Pathogenic:1

Apr 09, 2019

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This individual is heterozygous for the c.1370C>T variant in the ADAMTS13 gene which results in an amino acid substitution of proline to leucine at residue 457, p.(Pro457Leu). This variant has been previously reported as a compound heterozygote with another ADAMTS13 variant, in a patient with congenital thrombotic thrombocytopenic purpura (TTP) initially by Assink et al. 2003 Kidney Int 63:1995-9, PMID:12753286. The patient was shown to have less than 5% ADAMTS13 activity compared to 50% activity seen in the father who was heterozygous for the p.Pro457Leu variant (Manea et al. 2007 Eur J Pediatr 166:249-257 PMID:17187257). In vitro studies of the p.Pro457Leu mutant showed reduced activity compared to the wild type (Manea et al. 2007 Br J Haematol 138:651-652, PMID: 176227784). This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with an allele frequency of 0.57% (119 out of 20, 848 alleles Finnish European population). In silico analysis of pathogenicity (through Alamut Visual v2.8.1) using PolyPhen2, SIFT and MutationTaster all suggest that this variant is likely to be pathogenic. This variant is considered to be a likely pathogenic according to the ACMG guidelines (Evidence used: PS3, PM3, PP3). -

ADAMTS13-related disorder Uncertain:1

Feb 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ADAMTS13 c.1370C>T variant is predicted to result in the amino acid substitution p.Pro457Leu. This variant has been reported in the compound heterozygous state in individuals with thrombotic thrombocytopenic purpura (TTP) (see Patient 3 in Assink et al. 2003. PubMed ID: 12753286; Manea et al. 2007. PubMed ID: 17627784). Functional evidence indicates this variant affects secretion and activity of ADAMTS13 protein and therefore it is possible this variant increases susceptibility for TTP in heterozygous carriers (Katneni et al. 2017. PubMed ID: 28866379; Manea et al. 2007. PubMed ID: 17627784). This variant is reported in 0.57% of alleles in individuals of European (Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;T;.;.
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T;T;T;T
MetaRNN	Benign	0.021	T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.7	M;.;M;.
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-7.3	D;.;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.012	D;.;D;T
Sift4G	Uncertain	0.0030	D;D;D;.
Polyphen		1.0	D;.;D;D
Vest4		0.67
MVP		0.90
MPC		1.0
ClinPred		0.039	T
GERP RS		5.2
Varity_R		0.29
gMVP		0.79

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: rs36220240; hg19: chr9-136302010;