chr9-133428735-C-G

Variant names:

• chr9-133428735-C-G
• rs281875293
• NM_139027.6:c.788C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_139027.6(ADAMTS13):​c.788C>G​(p.Ser263Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 29)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.24
• Publications: 2 publications found

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)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6	c.788C>G	p.Ser263Cys	missense_variant	Exon 7 of 29	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.788C>G	p.Ser263Cys	missense_variant	Exon 7 of 29	1	NM_139027.6	ENSP00000347927.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 29

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

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UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D;T;.;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.77	T;T;T;T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.;.;H;H
PhyloP100		7.2
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.5	D;.;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;.;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;.
Polyphen		1.0	D;.;.;D;D
Vest4		0.85
MutPred		0.96		Gain of catalytic residue at S263 (P = 0.0077);.;Gain of catalytic residue at S263 (P = 0.0077);Gain of catalytic residue at S263 (P = 0.0077);Gain of catalytic residue at S263 (P = 0.0077);
MVP		0.97
MPC		1.1
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.76
gMVP		0.89
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs281875293; hg19: chr9-136293855;