rs281875304

Positions:

• chr9-133428649-C-A
• chr9-133428649-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.702C>A​(p.His234Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: -0.319

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 binding_site (size 0) in uniprot entity ATS13_HUMAN there are 4 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, 0.989
• PP5: Variant 9-133428649-C-A is Pathogenic according to our data. Variant chr9-133428649-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68826.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-133428649-C-A is described in UniProt as null. Variant chr9-133428649-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS13	NM_139027.6	c.702C>A	p.His234Gln	missense_variant	7/29	ENST00000355699.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.702C>A	p.His234Gln	missense_variant	7/29	1	NM_139027.6	A2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1200102 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 588392

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 04, 2022	PP3, PM1, PM2_supporting, PM3 -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;.;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	H;.;H;H
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.4	D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;.;D;D
Vest4		0.86
MutPred		0.91		Loss of catalytic residue at H234 (P = 0.0788);Loss of catalytic residue at H234 (P = 0.0788);Loss of catalytic residue at H234 (P = 0.0788);Loss of catalytic residue at H234 (P = 0.0788);
MVP		0.96
MPC		1.1
ClinPred		0.99	D
GERP RS		1.6
Varity_R		0.56
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs281875304; hg19: chr9-136293769;