dbSNP rs121908476: ADAMTS13:p.Gln449Glu (chr9-133436865-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_139027.6(ADAMTS13):c.1345C>G(p.Gln449Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,435,866 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. Synonymous variant affecting the same amino acid position (i.e. Q449Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

ADAMTS13
NM_139027.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.29

Publications

8 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6 link	c.1345C>G	p.Gln449Glu	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.1345C>G	p.Gln449Glu	missense_variant	Exon 12 of 29	1	NM_139027.6	ENSP00000347927.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000486

AC:

AN:

205952

AF XY:

0.00000898

show subpopulations

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

AF:

6.96e-7

AC:

AN:

1435866

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

711752

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33198

American (AMR)

AF:

0.00

AC:

AN:

41050

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25552

East Asian (EAS)

AF:

0.00

AC:

AN:

38812

South Asian (SAS)

AF:

0.0000121

AC:

AN:

82476

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099576

Other (OTH)

AF:

0.00

AC:

AN:

59370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;T;.;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.85

D;D;D;T

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.91

D;D;D;D

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

3.7

H;.;H;.

PhyloP100

6.3

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.0

D;.;D;D

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Uncertain

0.0050

D;D;D;.

Polyphen

1.0

D;.;D;D

Vest4

0.73

MutPred

0.67

Gain of relative solvent accessibility (P = 0.1571);.;Gain of relative solvent accessibility (P = 0.1571);.;

MVP

0.92

MPC

1.1

ClinPred

0.93

GERP RS

5.2

Varity_R

0.29

gMVP

0.95

Mutation Taster

=34/66

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over