Genetic Variant ADAMTS13:p.Gln448Lys (chr9-133436862-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_139027.6(ADAMTS13):c.1342C>A(p.Gln448Lys) 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 benign outcome for this variant. 16/22 in silico tools predict a benign 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. Q448E) has been classified as Benign.

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ADAMTS13
NM_139027.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.29

Publications

67 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22928101).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6 link	c.1342C>A	p.Gln448Lys	missense_variant	Exon 12 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.1342C>A	p.Gln448Lys	missense_variant	Exon 12 of 29	1	NM_139027.6	ENSP00000347927.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

207396

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1433124

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710298

African (AFR)

AF:

0.00

AC:

AN:

33020

American (AMR)

AF:

0.00

AC:

AN:

40964

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25466

East Asian (EAS)

AF:

0.00

AC:

AN:

38296

South Asian (SAS)

AF:

0.00

AC:

AN:

82564

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49918

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098036

Other (OTH)

AF:

0.00

AC:

AN:

59164

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.14

T;T;.;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.75

T;T;T;T

M_CAP

Benign

0.069

MetaRNN

Benign

0.23

T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.3

L;.;L;.

PhyloP100

3.3

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.86

N;.;N;N

REVEL

Benign

0.050

Sift

Benign

0.51

T;.;T;T

Sift4G

Benign

0.091

T;D;T;.

Polyphen

0.0070

B;.;B;B

Vest4

0.26

MutPred

0.42

Gain of ubiquitination at Q448 (P = 0.0138);.;Gain of ubiquitination at Q448 (P = 0.0138);.;

MVP

0.78

MPC

0.43

ClinPred

0.55

GERP RS

4.3

Varity_R

0.25

gMVP

0.74

Mutation Taster

=93/7

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over