9-133428750-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_139027.6(ADAMTS13):c.803G>C(p.Arg268Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000832 in 1,202,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.90

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a disulfide_bond (size 79) in uniprot entity ATS13_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_139027.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906
• PP5: Variant 9-133428750-G-C is Pathogenic according to our data. Variant chr9-133428750-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 5812.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-133428750-G-C is described in UniProt as null. Variant chr9-133428750-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS13	NM_139027.6	c.803G>C	p.Arg268Pro	missense_variant	7/29	ENST00000355699.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.803G>C	p.Arg268Pro	missense_variant	7/29	1	NM_139027.6	A2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 8.32e-7 AC: 1 AN: 1202134 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 588504

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: 0.00000102

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Upshaw-Schulman syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 03, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D;T;.;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.82	T;D;D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.5	M;.;.;M;M
MutationTaster	Benign	0.0045	A;A;A;A;A;A
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.3	D;.;D;D;N
REVEL	Uncertain	0.36
Sift	Benign	0.13	T;.;D;T;D
Sift4G	Uncertain	0.049	D;T;D;D;.
Polyphen		0.91	P;.;.;P;P
Vest4		0.47
MutPred		0.81		Loss of MoRF binding (P = 8e-04);.;Loss of MoRF binding (P = 8e-04);Loss of MoRF binding (P = 8e-04);Loss of MoRF binding (P = 8e-04);
MVP		0.86
MPC		0.52
ClinPred		0.93	D
GERP RS		1.0
Varity_R		0.85
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121908477; hg19: chr9-136293870;