rs28503257

Variant names:

• chr9-133454467-G-A
• rs28503257
• NM_139027.6:c.3097G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_139027.6(ADAMTS13):​c.3097G>A​(p.Ala1033Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0367 in 1,613,558 control chromosomes in the GnomAD database, including 1,340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (107 hom., cov: 33)
  • Exomes 𝑓: 0.037 (1233 hom.)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.99
• Publications: 25 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028647482).
• BP6: Variant 9-133454467-G-A is Benign according to our data. Variant chr9-133454467-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0303 (4618/152356) while in subpopulation NFE AF = 0.0402 (2737/68026). AF 95% confidence interval is 0.039. There are 107 homozygotes in GnomAd4. There are 2341 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 107 AR gene

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.3097G>A	p.Ala1033Thr	missense	Exon 24 of 29	NP_620596.2	Q76LX8-2
	ADAMTS13	NM_139025.5		c.3097G>A	p.Ala1033Thr	missense	Exon 24 of 29	NP_620594.1	Q76LX8-1
	ADAMTS13	NM_139026.6		c.3004G>A	p.Ala1002Thr	missense	Exon 24 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.3097G>A	p.Ala1033Thr	missense	Exon 24 of 29	ENSP00000347927.2	Q76LX8-2
	ADAMTS13	ENST00000371929.7	TSL:1	c.3097G>A	p.Ala1033Thr	missense	Exon 24 of 29	ENSP00000360997.3	Q76LX8-1
	ADAMTS13	ENST00000356589.6	TSL:1	c.3004G>A	p.Ala1002Thr	missense	Exon 24 of 29	ENSP00000348997.2	Q76LX8-3

Frequencies

GnomAD3 genomes AF: 0.0303 AC: 4616 AN: 152238 Hom.: 107 Cov.: 33

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.0727

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0402

Gnomad OTH AF: 0.0272

GnomAD2 exomes AF: 0.0308 AC: 7706 AN: 250526 AF XY: 0.0318

Gnomad AFR exome AF: 0.00869

Gnomad AMR exome AF: 0.0148

Gnomad ASJ exome AF: 0.0222

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0671

Gnomad NFE exome AF: 0.0404

Gnomad OTH exome AF: 0.0323

GnomAD4 exome AF: 0.0373 AC: 54545 AN: 1461202 Hom.: 1233 Cov.: 32 AF XY: 0.0369 AC XY: 26825 AN XY: 726930

African (AFR) AF: 0.00821 AC: 275 AN: 33478

American (AMR) AF: 0.0148 AC: 662 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 572 AN: 26132

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0210 AC: 1808 AN: 86258

European-Finnish (FIN) AF: 0.0657 AC: 3470 AN: 52776

Middle Eastern (MID) AF: 0.0297 AC: 171 AN: 5766

European-Non Finnish (NFE) AF: 0.0410 AC: 45637 AN: 1111990

Other (OTH) AF: 0.0322 AC: 1946 AN: 60380

GnomAD4 genome AF: 0.0303 AC: 4618 AN: 152356 Hom.: 107 Cov.: 33 AF XY: 0.0314 AC XY: 2341 AN XY: 74502

African (AFR) AF: 0.0104 AC: 432 AN: 41584

American (AMR) AF: 0.0223 AC: 342 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4830

European-Finnish (FIN) AF: 0.0727 AC: 772 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0402 AC: 2737 AN: 68026

Other (OTH) AF: 0.0270 AC: 57 AN: 2114

Alfa AF: 0.0346 Hom.: 339

Bravo AF: 0.0253

TwinsUK AF: 0.0378 AC: 140

ALSPAC AF: 0.0428 AC: 165

ESP6500AA AF: 0.00953 AC: 42

ESP6500EA AF: 0.0400 AC: 344

ExAC AF: 0.0317 AC: 3843

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0381

EpiControl AF: 0.0372

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Upshaw-Schulman syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.060	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.15
Sift	Benign	0.18	T
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.22
MPC		1.1
ClinPred		0.059	T
GERP RS		5.6
Varity_R		0.24
gMVP		0.57
Mutation Taster		=94/6	polymorphism (auto)

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: rs28503257; hg19: chr9-136319589; COSMIC: COSV99053403; COSMIC: COSV99053403;