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: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Orphanet

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139027.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS13	NM_139027.6	MANE Select	c.3548G>T	p.Gly1183Val	missense splice_region	Exon 27 of 29	NP_620596.2	Q76LX8-2
	ADAMTS13	NM_139025.5		c.3716G>T	p.Gly1239Val	missense splice_region	Exon 27 of 29	NP_620594.1	Q76LX8-1
	ADAMTS13	NM_139026.6		c.3455G>T	p.Gly1152Val	missense splice_region	Exon 27 of 29	NP_620595.1	Q76LX8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS13	ENST00000355699.7	TSL:1 MANE Select	c.3548G>T	p.Gly1183Val	missense splice_region	Exon 27 of 29	ENSP00000347927.2	Q76LX8-2
	ADAMTS13	ENST00000371929.7	TSL:1	c.3716G>T	p.Gly1239Val	missense splice_region	Exon 27 of 29	ENSP00000360997.3	Q76LX8-1
	ADAMTS13	ENST00000356589.6	TSL:1	c.3455G>T	p.Gly1152Val	missense splice_region	Exon 27 of 29	ENSP00000348997.2	Q76LX8-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.3
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	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;