chr9-133449850-TGTGCCC-T

Variant names:

• chr9-133449850-TGTGCCC-T
• rs387906346
• NM_139027.6:c.2931_2936delTGCCCG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4 PP5

The NM_139025.5(ADAMTS13):​c.2931_2936delTGCCCG​(p.Cys977_Arg979delinsTrp) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAMTS13 NM_139025.5 disruptive_inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.91
• Publications: 4 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
• PM4: Nonframeshift variant in NON repetitive region in NM_139025.5.
• PP5: Variant 9-133449850-TGTGCCC-T is Pathogenic according to our data. Variant chr9-133449850-TGTGCCC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 5821.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139025.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS13	NM_139027.6	MANE Select	c.2931_2936delTGCCCG	p.Cys977_Arg979delinsTrp	disruptive_inframe_deletion	Exon 23 of 29	NP_620596.2
	ADAMTS13	NM_139025.5		c.2931_2936delTGCCCG	p.Cys977_Arg979delinsTrp	disruptive_inframe_deletion	Exon 23 of 29	NP_620594.1
	ADAMTS13	NM_139026.6		c.2838_2843delTGCCCG	p.Cys946_Arg948delinsTrp	disruptive_inframe_deletion	Exon 23 of 29	NP_620595.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS13	ENST00000355699.7	TSL:1 MANE Select	c.2931_2936delTGCCCG	p.Cys977_Arg979delinsTrp	disruptive_inframe_deletion	Exon 23 of 29	ENSP00000347927.2
	ADAMTS13	ENST00000371929.7	TSL:1	c.2931_2936delTGCCCG	p.Cys977_Arg979delinsTrp	disruptive_inframe_deletion	Exon 23 of 29	ENSP00000360997.3
	ADAMTS13	ENST00000356589.6	TSL:1	c.2838_2843delTGCCCG	p.Cys946_Arg948delinsTrp	disruptive_inframe_deletion	Exon 23 of 29	ENSP00000348997.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250626 AF XY: 0.00000737

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Upshaw-Schulman syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.9
Mutation Taster		=11/189	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs387906346; hg19: chr9-136314971;