dbSNP rs281875304: ADAMTS13:p.His234Gln (chr9-133428649-C-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_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

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: -0.319

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain 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 VariationId is 68826.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139027.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAMTS13	NM_139027.6	MANE Select	c.702C>A	p.His234Gln	missense	Exon 7 of 29	NP_620596.2	Q76LX8-2
ADAMTS13	NM_139025.5		c.702C>A	p.His234Gln	missense	Exon 7 of 29	NP_620594.1	Q76LX8-1
ADAMTS13	NM_139026.6		c.702C>A	p.His234Gln	missense	Exon 7 of 29	NP_620595.1	Q76LX8-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAMTS13	ENST00000355699.7	TSL:1 MANE Select	c.702C>A	p.His234Gln	missense	Exon 7 of 29	ENSP00000347927.2	Q76LX8-2
ADAMTS13	ENST00000371929.7	TSL:1	c.702C>A	p.His234Gln	missense	Exon 7 of 29	ENSP00000360997.3	Q76LX8-1
ADAMTS13	ENST00000356589.6	TSL:1	c.702C>A	p.His234Gln	missense	Exon 7 of 29	ENSP00000348997.2	Q76LX8-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1200102

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

588392

African (AFR)

AF:

0.00

AC:

AN:

24224

American (AMR)

AF:

0.00

AC:

AN:

20580

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19408

East Asian (EAS)

AF:

0.00

AC:

AN:

24134

South Asian (SAS)

AF:

0.00

AC:

AN:

53900

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3332

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

979598

Other (OTH)

AF:

0.00

AC:

AN:

47680

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.72

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.71

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.6

PhyloP100

-0.32

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-7.4

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.86

MutPred

0.91

Loss of catalytic residue at H234 (P = 0.0788)

MVP

0.96

MPC

1.1

ClinPred

0.99

GERP RS

1.6

Varity_R

0.56

gMVP

0.90

Mutation Taster

=10/90

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over