rs281875303

Variant names:

• chr9-133456543-G-T
• rs281875303
• NM_139027.6:c.3548G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_139027.6(ADAMTS13):​c.3548G>T​(p.Gly1183Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1183R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADAMTS13 NM_139027.6 missense, splice_region
• Scores: Splicing: ADA: 0.9974
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 6.29
• Publications: 6 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-133456215-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3065326.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6	c.3548G>T	p.Gly1183Val	missense_variant, splice_region_variant	Exon 27 of 29	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.3548G>T	p.Gly1183Val	missense_variant, splice_region_variant	Exon 27 of 29	1	NM_139027.6	ENSP00000347927.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.;.;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;T;T;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.3	M;.;.;.
PhyloP100		6.3
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.1	D;D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;.;D
Polyphen		1.0	D;D;D;.
Vest4		0.69
MutPred		0.75		Loss of catalytic residue at M1241 (P = 0.0232);.;.;.;
MVP		0.98
MPC		1.0
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.20
gMVP		0.59
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: -41

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs281875303; hg19: chr9-136321665;