rs36220240

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 4P and 12B. PS3 BP4_Strong BS1 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). ClinVar reports functional evidence for this variant: "SCV000478320: in vitro studies showed impaired secretion and very low activity of the secreted variant proteins (Manea et al. 2007a" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P457P) has been classified as Likely benign.

• 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:8 B:1
• Conservation: PhyloP100: 4.64
• Publications: 14 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: Benign. The variant received -8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000478320: in vitro studies showed impaired secretion and very low activity of the secreted variant proteins (Manea et al. 2007a; Manea et al. 2007b).; SCV001449176: 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).
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

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.1370C>T	p.Pro457Leu	missense	Exon 12 of 29	NP_620596.2	Q76LX8-2
	ADAMTS13	NM_139025.5		c.1370C>T	p.Pro457Leu	missense	Exon 12 of 29	NP_620594.1	Q76LX8-1
	ADAMTS13	NM_139026.6		c.1277C>T	p.Pro426Leu	missense	Exon 12 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.1370C>T	p.Pro457Leu	missense	Exon 12 of 29	ENSP00000347927.2	Q76LX8-2
	ADAMTS13	ENST00000371929.7	TSL:1	c.1370C>T	p.Pro457Leu	missense	Exon 12 of 29	ENSP00000360997.3	Q76LX8-1
	ADAMTS13	ENST00000356589.6	TSL:1	c.1277C>T	p.Pro426Leu	missense	Exon 12 of 29	ENSP00000348997.2	Q76LX8-3

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

GnomAD2 exomes AF: 0.00226 AC: 458 AN: 202740 AF XY: 0.00220

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 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

African (AFR) AF: 0.000572 AC: 19 AN: 33244

American (AMR) AF: 0.00143 AC: 58 AN: 40674

Ashkenazi Jewish (ASJ) AF: 0.0000391 AC: 1 AN: 25548

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38776

South Asian (SAS) AF: 0.000401 AC: 33 AN: 82340

European-Finnish (FIN) AF: 0.00524 AC: 262 AN: 50002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00234 AC: 2576 AN: 1099572

Other (OTH) AF: 0.00177 AC: 105 AN: 59332

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

African (AFR) AF: 0.000434 AC: 18 AN: 41492

American (AMR) AF: 0.00439 AC: 67 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5148

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00416 AC: 44 AN: 10584

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

European-Non Finnish (NFE) AF: 0.00247 AC: 168 AN: 67982

Other (OTH) AF: 0.00380 AC: 8 AN: 2104

Alfa AF: 0.00196 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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	2	-	Upshaw-Schulman syndrome (4)
-	2	1	not provided (3)
-	3	-	not specified (3)
-	1	-	ADAMTS13-related disorder (1)
1	-	-	Atypical hemolytic-uremic syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.021	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.6
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	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
Mutation Taster		=66/34	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: rs36220240; hg19: chr9-136302010;