rs121908477

Variant names:

• chr9-133428750-G-C
• rs121908477
• NM_139027.6:c.803G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-133428750-G-C
• chr9-133428750-G-A
• chr9-133428750-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_139027.6(ADAMTS13):​c.803G>C​(p.Arg268Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000832 in 1,202,134 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).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.90
• 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906
• PP5: Variant 9-133428750-G-C is Pathogenic according to our data. Variant chr9-133428750-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 5812.Status of the report is no_assertion_criteria_provided, 0 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.803G>C	p.Arg268Pro	missense	Exon 7 of 29	NP_620596.2	Q76LX8-2
	ADAMTS13	NM_139025.5		c.803G>C	p.Arg268Pro	missense	Exon 7 of 29	NP_620594.1	Q76LX8-1
	ADAMTS13	NM_139026.6		c.803G>C	p.Arg268Pro	missense	Exon 7 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.803G>C	p.Arg268Pro	missense	Exon 7 of 29	ENSP00000347927.2	Q76LX8-2
	ADAMTS13	ENST00000371929.7	TSL:1	c.803G>C	p.Arg268Pro	missense	Exon 7 of 29	ENSP00000360997.3	Q76LX8-1
	ADAMTS13	ENST00000356589.6	TSL:1	c.803G>C	p.Arg268Pro	missense	Exon 7 of 29	ENSP00000348997.2	Q76LX8-3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 8.32e-7 AC: 1 AN: 1202134 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 588504

African (AFR) AF: 0.00 AC: 0 AN: 24566

American (AMR) AF: 0.00 AC: 0 AN: 20458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19220

East Asian (EAS) AF: 0.00 AC: 0 AN: 24968

South Asian (SAS) AF: 0.00 AC: 0 AN: 53024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26814

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3336

European-Non Finnish (NFE) AF: 0.00000102 AC: 1 AN: 981654

Other (OTH) AF: 0.00 AC: 0 AN: 48094

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

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
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.36
Sift	Benign	0.13	T
Sift4G	Uncertain	0.049	D
Polyphen		0.91	P
Vest4		0.47
MutPred		0.81		Loss of MoRF binding (P = 8e-04)
MVP		0.86
MPC		0.52
ClinPred		0.93	D
GERP RS		1.0
Varity_R		0.85
gMVP		0.78
Mutation Taster		=27/73	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121908477; hg19: chr9-136293870;