Genetic Variant ADAMTS13:p.Ser263Tyr (chr9-133428735-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_139027.6(ADAMTS13):c.788C>A(p.Ser263Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000221 in 1,358,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S263C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 29)

Exomes 𝑓: 8.3e-7 ( 0 hom. )

Consequence

ADAMTS13
NM_139027.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.24

Publications

2 publications found

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 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)

ADAMTS13 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6 link	c.788C>A	p.Ser263Tyr	missense_variant	Exon 7 of 29	ENST00000355699.7	NP_620596.2	Q76LX8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7 link	c.788C>A	p.Ser263Tyr	missense_variant	Exon 7 of 29	1	NM_139027.6	ENSP00000347927.2		Q76LX8-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151538

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

8.29e-7

AC:

AN:

1206880

Hom.:

Cov.:

AF XY:

0.00000169

AC XY:

AN XY:

591104

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24608

American (AMR)

AF:

0.00

AC:

AN:

20400

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19436

East Asian (EAS)

AF:

0.00

AC:

AN:

25174

South Asian (SAS)

AF:

0.00

AC:

AN:

53542

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27068

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3374

European-Non Finnish (NFE)

AF:

0.00000102

AC:

AN:

984880

Other (OTH)

AF:

0.00

AC:

AN:

48398

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.825

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151538

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74004

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41306

American (AMR)

AF:

0.00

AC:

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10440

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67782

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

D;T;.;.;.

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.82

T;D;D;D;D

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;.;.;H;H

PhyloP100

7.2

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-5.4

D;.;D;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;.;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;.

Polyphen

1.0

D;.;.;D;D

Vest4

0.87

MutPred

0.94

Gain of catalytic residue at S263 (P = 0.0222);.;Gain of catalytic residue at S263 (P = 0.0222);Gain of catalytic residue at S263 (P = 0.0222);Gain of catalytic residue at S263 (P = 0.0222);

MVP

0.97

MPC

1.2

ClinPred

1.0

GERP RS

4.0

Varity_R

0.87

gMVP

0.92

Mutation Taster

=3/97

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over