rs121908474

Variant names:

• chr9-133456138-G-A
• rs121908474
• NM_139027.6:c.3470G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-133456138-G-A
• chr9-133456138-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_139027.6(ADAMTS13):​c.3470G>A​(p.Cys1157Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,262 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1157R) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.98
• 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-133456137-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3894576.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 9-133456138-G-A is Pathogenic according to our data. Variant chr9-133456138-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 5808.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6	c.3470G>A	p.Cys1157Tyr	missense_variant	Exon 26 of 29	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.3470G>A	p.Cys1157Tyr	missense_variant	Exon 26 of 29	1	NM_139027.6	ENSP00000347927.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152262 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74390

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Upshaw-Schulman syndrome Pathogenic:1

Oct 04, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.;.;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.3	M;.;.;.
PhyloP100		7.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-8.4	D;D;D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;D;D;.
Vest4		0.83
MutPred		0.75		Gain of phosphorylation at C1213 (P = 0.042);.;.;.;
MVP		0.97
MPC		1.4
ClinPred		0.99	D
GERP RS		5.1
PromoterAI		-0.0085	Neutral
Varity_R		0.45
gMVP		0.92
Mutation Taster		=5/95	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: rs121908474; hg19: chr9-136321260;