rs281875291

Positions:

• chr9-133425554-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_139027.6(ADAMTS13):​c.356C>T​(p.Ser119Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S119S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 4.11

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 10 ACMG points.

• PM1: In a domain Peptidase M12B (size 206) in uniprot entity ATS13_HUMAN there are 26 pathogenic changes around while only 4 benign (87%) in NM_139027.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 9-133425554-C-T is Pathogenic according to our data. Variant chr9-133425554-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68817.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-133425554-C-T is described in UniProt as null. Variant chr9-133425554-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS13	NM_139027.6	c.356C>T	p.Ser119Phe	missense_variant	4/29	ENST00000355699.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.356C>T	p.Ser119Phe	missense_variant	4/29	1	NM_139027.6	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Jan 01, 2020

- -

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.5	M;.;M;M
MutationTaster	Benign	0.92	N;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.1	D;D;D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;.
Polyphen		0.98	D;.;D;D
Vest4		0.56
MutPred		0.97		Loss of disorder (P = 0.0719);Loss of disorder (P = 0.0719);Loss of disorder (P = 0.0719);Loss of disorder (P = 0.0719);
MVP		0.93
MPC		1.1
ClinPred		0.99	D
GERP RS		2.6
Varity_R		0.15
gMVP		0.77

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: rs281875291; hg19: chr9-136290674;