Variant rs121908478 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The ENST00000355699.7(ADAMTS13):c.749C>T(p.Ala250Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000825 in 1,211,588 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
ENST00000355699.7 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.56

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a disulfide_bond (size 23) in uniprot entity ATS13_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000355699.7

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.948

PP5

Variant 9-133428696-C-T is Pathogenic according to our data. Variant chr9-133428696-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5818.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-133428696-C-T is described in UniProt as null. Variant chr9-133428696-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS13	NM_139027.6 linkuse as main transcript	c.749C>T	p.Ala250Val	missense_variant	7/29	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7 linkuse as main transcript	c.749C>T	p.Ala250Val	missense_variant	7/29	1	NM_139027.6	ENSP00000347927	A2	Q76LX8-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.25e-7

AC:

AN:

1211588

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

594154

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000398

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.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Upshaw-Schulman syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;T;.;.;.

Eigen

Benign

0.11

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.84

T;T;D;D;D

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.95

D;D;D;D;D

MetaSVM

Uncertain

0.58

MutationAssessor

Uncertain

2.4

M;.;.;M;M

MutationTaster

Benign

0.76

A;A;A;A;A;A

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.5

D;.;D;D;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0030

D;.;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D;.

Polyphen

1.0

D;.;.;D;D

Vest4

0.46

MutPred

0.87

Loss of disorder (P = 0.1637);.;Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);Loss of disorder (P = 0.1637);

MVP

0.92

MPC

1.0

ClinPred

0.98

GERP RS

-0.46

Varity_R

0.25

gMVP

0.75

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over