rs281875298

chr9-133426266-T-Achr9-133426266-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_139027.6(ADAMTS13):c.607T>A(p.Ser203Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. S203P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.77

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a disulfide_bond (size 79) in uniprot entity ATS13_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_139027.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-133426266-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.789

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS13	NM_139027.6	c.607T>A	p.Ser203Thr	missense_variant	6/29	ENST00000355699.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.607T>A	p.Ser203Thr	missense_variant	6/29	1	NM_139027.6	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	0.0075	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.8	L;.;L;L
MutationTaster	Benign	0.97	D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Uncertain	0.58
Sift	Uncertain	0.016	D;T;D;D
Sift4G	Uncertain	0.0070	D;D;D;.
Polyphen		1.0	D;.;D;D
Vest4		0.49
MutPred		0.72		Gain of glycosylation at P204 (P = 0.4058);Gain of glycosylation at P204 (P = 0.4058);Gain of glycosylation at P204 (P = 0.4058);Gain of glycosylation at P204 (P = 0.4058);
MVP		0.90
MPC		0.91
ClinPred		0.91	D
GERP RS		4.7
Varity_R		0.28
gMVP		0.59

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: rs281875298; hg19: chr9-136291386;