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

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Variant links:

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)

ADAMTS13 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6 link	c.686+4T>G		splice_region_variant, intron_variant	Intron 6 of 28	ENST00000355699.7	NP_620596.2	Q76LX8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7 link	c.686+4T>G		splice_region_variant, intron_variant	Intron 6 of 28	1	NM_139027.6	ENSP00000347927.2		Q76LX8-2

Frequencies

GnomAD3 genomes

AF:

0.0561

AC:

8536

AN:

152082

Hom.:

342

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0748

AC XY:

53910

AN XY:

720616

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

6473

12946

19419

25892

32365

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3522

7044

10566

14088

17610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0561

AC:

8532

AN:

152200

Hom.:

341

Cov.:

AF XY:

0.0550

AC XY:

4092

AN XY:

74414

show subpopulations

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:

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.0892

AC:

6062

AN:

67990

Other (OTH)

AF:

0.0568

AC:

120

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

420

840

1259

1679

2099

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

294

392

490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0666

Hom.:

109

Bravo

AF:

0.0541

Asia WGS

AF:

0.0150

AC:

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

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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) -

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

5.6

(source)

DANN

Benign

0.37

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over