NM_139027.6:c.686+4T>G

Variant names:

• chr9-133426349-T-G
• rs36219245
• NM_139027.6:c.686+4T>G

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.686+4T>G variant causes a splice 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.00008326
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.13
• Publications: 3 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=-0.85).
• BP6: Variant 9-133426349-T-G is Benign according to our data. Variant chr9-133426349-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0873 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.686+4T>G		splice_region intron	N/A	NP_620596.2
	ADAMTS13	NM_139025.5		c.686+4T>G		splice_region intron	N/A	NP_620594.1
	ADAMTS13	NM_139026.6		c.686+4T>G		splice_region 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.686+4T>G		splice_region intron	N/A	ENSP00000347927.2
	ADAMTS13	ENST00000371929.7	TSL:1	c.686+4T>G		splice_region intron	N/A	ENSP00000360997.3
	ADAMTS13	ENST00000356589.6	TSL:1	c.686+4T>G		splice_region intron	N/A	ENSP00000348997.2

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

GnomAD2 exomes AF: 0.0580 AC: 13946 AN: 240260 AF XY: 0.0586

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 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

African (AFR) AF: 0.0126 AC: 422 AN: 33476

American (AMR) AF: 0.0335 AC: 1499 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0693 AC: 1811 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.0211 AC: 1823 AN: 86250

European-Finnish (FIN) AF: 0.0585 AC: 2307 AN: 39462

Middle Eastern (MID) AF: 0.0594 AC: 342 AN: 5762

European-Non Finnish (NFE) AF: 0.0888 AC: 98754 AN: 1111894

Other (OTH) AF: 0.0675 AC: 4068 AN: 60294

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

African (AFR) AF: 0.0155 AC: 643 AN: 41536

American (AMR) AF: 0.0474 AC: 724 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0732 AC: 254 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.0213 AC: 103 AN: 4826

European-Finnish (FIN) AF: 0.0565 AC: 599 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0892 AC: 6062 AN: 67990

Other (OTH) AF: 0.0568 AC: 120 AN: 2114

Alfa AF: 0.0666 Hom.: 109

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26284228)

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely 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

Upshaw-Schulman syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely 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	-0.85
CADD	Benign	5.6
DANN	Benign	0.37
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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