dbSNP rs281875292: ADAMTS13:p.Leu232Gln (chr9-133428642-T-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_139027.6(ADAMTS13):c.695T>A(p.Leu232Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000882 in 1,133,584 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 not provided (no stars).

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 8.8e-7 ( 0 hom. )

Consequence

ADAMTS13
NM_139027.6 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 5.71

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 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, 5 uncertain in NM_139027.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6 link	c.695T>A	p.Leu232Gln	missense_variant	Exon 7 of 29	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7 link	c.695T>A	p.Leu232Gln	missense_variant	Exon 7 of 29	1	NM_139027.6	ENSP00000347927.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.82e-7

AC:

AN:

1133584

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

553644

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

22516

American (AMR)

AF:

0.00

AC:

AN:

18358

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17278

East Asian (EAS)

AF:

0.00

AC:

AN:

19790

South Asian (SAS)

AF:

0.00

AC:

AN:

52020

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20896

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2966

European-Non Finnish (NFE)

AF:

0.00000107

AC:

AN:

936372

Other (OTH)

AF:

0.00

AC:

AN:

43388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

not provided

Other:1

UniProtKB/Swiss-Prot

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

D;.;.;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.85

D;T;D;T

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Uncertain

-0.20

MutationAssessor

Uncertain

2.4

M;.;M;M

PhyloP100

5.7

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-4.2

D;D;D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;.

Polyphen

1.0

D;.;D;D

Vest4

0.42

MutPred

0.94

Loss of stability (P = 0.0305);Loss of stability (P = 0.0305);Loss of stability (P = 0.0305);Loss of stability (P = 0.0305);

MVP

0.93

MPC

1.0

ClinPred

0.98

GERP RS

3.5

Varity_R

0.65

gMVP

0.77

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over