rs36219245

chr9-133426349-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_139027.6(ADAMTS13):c.686+4T>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0747 in 1,599,886 control chromosomes in the GnomAD database, including 5,192 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (341 hom., cov: 33)
  • Exomes 𝑓: 0.077 (4851 hom.)
• Consequence: ADAMTS13 NM_139027.6 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00008326
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.13

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 9-133426349-T-G is Benign according to our data. Variant chr9-133426349-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 262453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133426349-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0873 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS13	NM_139027.6	c.686+4T>G		splice_donor_region_variant, intron_variant		ENST00000355699.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.686+4T>G		splice_donor_region_variant, intron_variant		1	NM_139027.6	A2

Frequencies

GnomAD3 genomes AF: 0.0561 AC: 8536 AN: 152082 Hom.: 342 Cov.: 33

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.0474

Gnomad ASJ AF: 0.0732

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.0565

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0892

Gnomad OTH AF: 0.0578

GnomAD3 exomes AF: 0.0580 AC: 13946 AN: 240260 Hom.: 585 AF XY: 0.0586 AC XY: 7664 AN XY: 130844

Gnomad AFR exome AF: 0.0147

Gnomad AMR exome AF: 0.0321

Gnomad ASJ exome AF: 0.0702

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0212

Gnomad FIN exome AF: 0.0572

Gnomad NFE exome AF: 0.0902

Gnomad OTH exome AF: 0.0651

GnomAD4 exome AF: 0.0767 AC: 111029 AN: 1447686 Hom.: 4851 Cov.: 36 AF XY: 0.0748 AC XY: 53910 AN XY: 720616

Gnomad4 AFR exome AF: 0.0126

Gnomad4 AMR exome AF: 0.0335

Gnomad4 ASJ exome AF: 0.0693

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0211

Gnomad4 FIN exome AF: 0.0585

Gnomad4 NFE exome AF: 0.0888

Gnomad4 OTH exome AF: 0.0675

GnomAD4 genome AF: 0.0561 AC: 8532 AN: 152200 Hom.: 341 Cov.: 33 AF XY: 0.0550 AC XY: 4092 AN XY: 74414

Gnomad4 AFR AF: 0.0155

Gnomad4 AMR AF: 0.0474

Gnomad4 ASJ AF: 0.0732

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0213

Gnomad4 FIN AF: 0.0565

Gnomad4 NFE AF: 0.0892

Gnomad4 OTH AF: 0.0568

Alfa AF: 0.0711 Hom.: 105

Bravo AF: 0.0541

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.0858

EpiControl AF: 0.0875

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 26284228) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Upshaw-Schulman syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	5.6
Dann	Benign	0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000083
dbscSNV1_RF	Benign	0.0020
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

Publications

LitVar

Other links and lift over

dbSNP: rs36219245; hg19: chr9-136291469; COSMIC: COSV63020676;