NM_139027.6:c.2017A>T

Variant names:

• chr9-133442447-A-T
• rs281875307
• NM_139027.6:c.2017A>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3 PM2 PP3_Moderate PP5_Moderate

The NM_139027.6(ADAMTS13):​c.2017A>T​(p.Ile673Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000916253: "The p.Ile673Phe variant protein was shown to be produced in normal amounts, but expression analysis in HeLa cells demonstrated absent secretion from cells, as is normal for the wild type protein (Matsumoto et al. 2004)."".

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 0.686
• Publications: 7 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: Pathogenic. The variant received 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000916253: "The p.Ile673Phe variant protein was shown to be produced in normal amounts, but expression analysis in HeLa cells demonstrated absent secretion from cells, as is normal for the wild type protein (Matsumoto et al. 2004)."
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891
• PP5: Variant 9-133442447-A-T is Pathogenic according to our data. Variant chr9-133442447-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 68809.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2017A>T	p.Ile673Phe	missense	Exon 17 of 29	NP_620596.2	Q76LX8-2
	ADAMTS13	NM_139025.5		c.2017A>T	p.Ile673Phe	missense	Exon 17 of 29	NP_620594.1	Q76LX8-1
	ADAMTS13	NM_139026.6		c.1924A>T	p.Ile642Phe	missense	Exon 17 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.2017A>T	p.Ile673Phe	missense	Exon 17 of 29	ENSP00000347927.2	Q76LX8-2
	ADAMTS13	ENST00000371929.7	TSL:1	c.2017A>T	p.Ile673Phe	missense	Exon 17 of 29	ENSP00000360997.3	Q76LX8-1
	ADAMTS13	ENST00000356589.6	TSL:1	c.1924A>T	p.Ile642Phe	missense	Exon 17 of 29	ENSP00000348997.2	Q76LX8-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251280 AF XY: 0.00000736

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461562 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727088

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Upshaw-Schulman syndrome (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	0.017
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.69
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.47
MutPred		0.76		Gain of phosphorylation at Y677 (P = 0.1233)
MVP		0.90
MPC		1.3
ClinPred		0.91	D
GERP RS		1.6
Varity_R		0.14
gMVP		0.86
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs281875307; hg19: chr9-136307568;