rs121908476

Positions:

• chr9-133436865-C-G
• chr9-133436865-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_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.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.29

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a region_of_interest Cysteine-rich (size 116) in uniprot entity ATS13_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_139027.6
• 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/exons	MANE	Protein	UniProt
ADAMTS13	NM_139027.6	c.1345C>G	p.Gln449Glu	missense_variant	12/29	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.1345C>G	p.Gln449Glu	missense_variant	12/29	1	NM_139027.6	ENSP00000347927.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000486 AC: 1 AN: 205952 Hom.: 0 AF XY: 0.00000898 AC XY: 1 AN XY: 111298

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 SAS exome AF: 0.0000381

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: 1 AN: 1435866 Hom.: 0 Cov.: 35 AF XY: 0.00000140 AC XY: 1 AN XY: 711752

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: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;T;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D;D;D;T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.7	H;.;H;.
PrimateAI	Uncertain	0.50	T
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	D
GERP RS		5.2
Varity_R		0.29
gMVP		0.95

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

LitVar

Other links and lift over

dbSNP: rs121908476; hg19: chr9-136301985;