rs34100568

Variant names:

• chr9-133454374-G-A
• rs34100568
• NM_139027.6:c.3045-41G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_139027.6(ADAMTS13):​c.3045-41G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0437 in 1,608,612 control chromosomes in the GnomAD database, including 1,784 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (104 hom., cov: 33)
  • Exomes 𝑓: 0.045 (1680 hom.)
• Consequence: ADAMTS13 NM_139027.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.56
• Publications: 1 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 (BayesDel_noAF=-0.9).
• BP6: Variant 9-133454374-G-A is Benign according to our data. Variant chr9-133454374-G-A is described in ClinVar as Benign. ClinVar VariationId is 262439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0517 is higher than 0.05.

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.3045-41G>A		intron	N/A	NP_620596.2
	ADAMTS13	NM_139025.5		c.3045-41G>A		intron	N/A	NP_620594.1
	ADAMTS13	NM_139026.6		c.2952-41G>A		intron	N/A	NP_620595.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS13	ENST00000355699.7	TSL:1 MANE Select	c.3045-41G>A		intron	N/A	ENSP00000347927.2
	ADAMTS13	ENST00000371929.7	TSL:1	c.3045-41G>A		intron	N/A	ENSP00000360997.3
	ADAMTS13	ENST00000356589.6	TSL:1	c.2952-41G>A		intron	N/A	ENSP00000348997.2

Frequencies

GnomAD3 genomes AF: 0.0326 AC: 4965 AN: 152188 Hom.: 105 Cov.: 33

Gnomad AFR AF: 0.0100

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.0374

Gnomad ASJ AF: 0.0527

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.0197

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0499

Gnomad OTH AF: 0.0407

GnomAD2 exomes AF: 0.0324 AC: 8053 AN: 248176 AF XY: 0.0333

Gnomad AFR exome AF: 0.00929

Gnomad AMR exome AF: 0.0225

Gnomad ASJ exome AF: 0.0528

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0176

Gnomad NFE exome AF: 0.0496

Gnomad OTH exome AF: 0.0407

GnomAD4 exome AF: 0.0448 AC: 65264 AN: 1456306 Hom.: 1680 Cov.: 31 AF XY: 0.0438 AC XY: 31745 AN XY: 724838

African (AFR) AF: 0.00824 AC: 275 AN: 33372

American (AMR) AF: 0.0240 AC: 1072 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0506 AC: 1322 AN: 26106

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39654

South Asian (SAS) AF: 0.0150 AC: 1294 AN: 86044

European-Finnish (FIN) AF: 0.0169 AC: 886 AN: 52278

Middle Eastern (MID) AF: 0.0493 AC: 284 AN: 5760

European-Non Finnish (NFE) AF: 0.0520 AC: 57648 AN: 1108128

Other (OTH) AF: 0.0412 AC: 2481 AN: 60248

GnomAD4 genome AF: 0.0326 AC: 4962 AN: 152306 Hom.: 104 Cov.: 33 AF XY: 0.0320 AC XY: 2384 AN XY: 74478

African (AFR) AF: 0.0100 AC: 416 AN: 41566

American (AMR) AF: 0.0374 AC: 572 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0527 AC: 183 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0145 AC: 70 AN: 4826

European-Finnish (FIN) AF: 0.0197 AC: 209 AN: 10626

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0498 AC: 3388 AN: 68014

Other (OTH) AF: 0.0403 AC: 85 AN: 2108

Alfa AF: 0.0407 Hom.: 49

Bravo AF: 0.0337

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.12
DANN	Benign	0.56
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs34100568; hg19: chr9-136319496; COSMIC: COSV107438273; COSMIC: COSV107438273;