chr9-133424273-G-A

Variant names:

• chr9-133424273-G-A
• rs35194094
• NM_139027.6:c.173-48G>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.173-48G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0723 in 1,605,832 control chromosomes in the GnomAD database, including 4,876 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (325 hom., cov: 32)
  • Exomes 𝑓: 0.074 (4551 hom.)
• Consequence: ADAMTS13 NM_139027.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.32
• Publications: 2 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=-0.97).
• BP6: Variant 9-133424273-G-A is Benign according to our data. Variant chr9-133424273-G-A is described in ClinVar as Benign. ClinVar VariationId is 262428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0847 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS13	NM_139027.6	MANE Select	c.173-48G>A		intron	N/A	NP_620596.2
	ADAMTS13	NM_139025.5		c.173-48G>A		intron	N/A	NP_620594.1
	ADAMTS13	NM_139026.6		c.173-48G>A		intron	N/A	NP_620595.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS13	ENST00000355699.7	TSL:1 MANE Select	c.173-48G>A		intron	N/A	ENSP00000347927.2
	ADAMTS13	ENST00000371929.7	TSL:1	c.173-48G>A		intron	N/A	ENSP00000360997.3
	ADAMTS13	ENST00000356589.6	TSL:1	c.173-48G>A		intron	N/A	ENSP00000348997.2

Frequencies

GnomAD3 genomes AF: 0.0548 AC: 8334 AN: 152002 Hom.: 326 Cov.: 32

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0478

Gnomad ASJ AF: 0.0732

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0195

Gnomad FIN AF: 0.0547

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0866

Gnomad OTH AF: 0.0556

GnomAD2 exomes AF: 0.0560 AC: 13661 AN: 243800 AF XY: 0.0568

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.0336

Gnomad ASJ exome AF: 0.0714

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0546

Gnomad NFE exome AF: 0.0868

Gnomad OTH exome AF: 0.0636

GnomAD4 exome AF: 0.0741 AC: 107742 AN: 1453712 Hom.: 4551 Cov.: 34 AF XY: 0.0724 AC XY: 52397 AN XY: 723446

African (AFR) AF: 0.0123 AC: 411 AN: 33412

American (AMR) AF: 0.0349 AC: 1561 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0696 AC: 1819 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0200 AC: 1726 AN: 86168

European-Finnish (FIN) AF: 0.0547 AC: 2608 AN: 47638

Middle Eastern (MID) AF: 0.0527 AC: 224 AN: 4250

European-Non Finnish (NFE) AF: 0.0858 AC: 95381 AN: 1111536

Other (OTH) AF: 0.0666 AC: 4009 AN: 60170

GnomAD4 genome AF: 0.0548 AC: 8330 AN: 152120 Hom.: 325 Cov.: 32 AF XY: 0.0535 AC XY: 3975 AN XY: 74346

African (AFR) AF: 0.0150 AC: 622 AN: 41502

American (AMR) AF: 0.0478 AC: 731 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0732 AC: 254 AN: 3472

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5134

South Asian (SAS) AF: 0.0197 AC: 95 AN: 4818

European-Finnish (FIN) AF: 0.0547 AC: 580 AN: 10598

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0866 AC: 5888 AN: 67994

Other (OTH) AF: 0.0546 AC: 115 AN: 2108

Alfa AF: 0.0741 Hom.: 143

Bravo AF: 0.0534

Asia WGS AF: 0.0150 AC: 52 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.013
DANN	Benign	0.67
PhyloP100		-2.3
Mutation Taster		=100/0	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: rs35194094; hg19: chr9-136289393; COSMIC: COSV63020642;