9-133433478-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_139027.6(ADAMTS13):​c.1193G>T​(p.Arg398Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,266 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R398H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 30)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ADAMTS13
NM_139027.6 missense

Scores

8
8
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.00
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr9-133433478-G-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADAMTS13NM_139027.6 linkc.1193G>T p.Arg398Leu missense_variant Exon 10 of 29 ENST00000355699.7 NP_620596.2 Q76LX8-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADAMTS13ENST00000355699.7 linkc.1193G>T p.Arg398Leu missense_variant Exon 10 of 29 1 NM_139027.6 ENSP00000347927.2 Q76LX8-2

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461266
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
726892
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000189
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.77
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.17
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.40
T;T;.;.
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.88
D;D;D;D
M_CAP
Uncertain
0.28
D
MetaRNN
Pathogenic
0.95
D;D;D;D
MetaSVM
Benign
-0.30
T
MutationAssessor
Uncertain
2.4
M;.;M;.
PrimateAI
Uncertain
0.55
T
PROVEAN
Pathogenic
-6.7
D;.;D;D
REVEL
Uncertain
0.56
Sift
Uncertain
0.0020
D;.;D;D
Sift4G
Uncertain
0.0030
D;D;D;.
Polyphen
1.0
D;.;D;D
Vest4
0.82
MutPred
0.77
Loss of MoRF binding (P = 0.0219);.;Loss of MoRF binding (P = 0.0219);.;
MVP
0.88
MPC
1.2
ClinPred
0.99
D
GERP RS
4.9
Varity_R
0.74
gMVP
0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-136298598; API