Genetic Variant NM_139027.6:c.749C>T (chr9-133428696-C-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_139027.6(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
NM_139027.6 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.56

Publications

5 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 7 ACMG points.

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 VariationId is 5818.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6 link	c.749C>T	p.Ala250Val	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.749C>T	p.Ala250Val	missense_variant	Exon 7 of 29	1	NM_139027.6	ENSP00000347927.2

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

African (AFR)

AF:

0.00

AC:

AN:

24572

American (AMR)

AF:

0.00

AC:

AN:

20190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19582

East Asian (EAS)

AF:

0.0000398

AC:

AN:

25142

South Asian (SAS)

AF:

0.00

AC:

AN:

54850

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27674

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3386

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

987586

Other (OTH)

AF:

0.00

AC:

AN:

48606

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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.:

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

Oct 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

(source)

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

PhyloP100

2.6

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

Mutation Taster

=2/98

disease causing (ClinVar)

(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

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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