Genetic Variant ADAMTS13:c.3045-48T>C (chr9-133454367-T-C) – ACMG Classification: Benign (-20 pts)

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.3045-48T>C 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 1,604,582 control chromosomes in the GnomAD database, including 1,780 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 ( 1676 hom. )

Consequence

ADAMTS13
NM_139027.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.13

Publications

1 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=-0.92).

BP6

Variant 9-133454367-T-C is Benign according to our data. Variant chr9-133454367-T-C is described in ClinVar as Benign. ClinVar VariationId is 262440.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6 link	c.3045-48T>C		intron_variant	Intron 23 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.3045-48T>C		intron_variant	Intron 23 of 28	1	NM_139027.6	ENSP00000347927.2		Q76LX8-2

Frequencies

GnomAD3 genomes

AF:

0.0326

AC:

4965

AN:

152172

Hom.:

105

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0101

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.0374

Gnomad ASJ

AF:

0.0527

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0145

Gnomad FIN

AF:

0.0197

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0498

Gnomad OTH

AF:

0.0407

GnomAD2 exomes

AF:

0.0324

AC:

8042

AN:

247840

AF XY:

0.0333

show subpopulations

Gnomad AFR exome

AF:

0.00923

Gnomad AMR exome

AF:

0.0225

Gnomad ASJ exome

AF:

0.0527

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0176

Gnomad NFE exome

AF:

0.0497

Gnomad OTH exome

AF:

0.0407

GnomAD4 exome

AF:

0.0448

AC:

65108

AN:

1452292

Hom.:

1676

Cov.:

AF XY:

0.0438

AC XY:

31687

AN XY:

723160

show subpopulations

African (AFR)

AF:

0.00820

AC:

273

AN:

33276

American (AMR)

AF:

0.0240

AC:

1071

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.0506

AC:

1320

AN:

26080

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39624

South Asian (SAS)

AF:

0.0150

AC:

1291

AN:

85924

European-Finnish (FIN)

AF:

0.0170

AC:

885

AN:

52070

Middle Eastern (MID)

AF:

0.0498

AC:

286

AN:

5740

European-Non Finnish (NFE)

AF:

0.0520

AC:

57500

AN:

1104772

Other (OTH)

AF:

0.0413

AC:

2480

AN:

60108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

3178

6356

9533

12711

15889

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2140

4280

6420

8560

10700

<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:

0.0326

AC:

4962

AN:

152290

Hom.:

104

Cov.:

AF XY:

0.0320

AC XY:

2382

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0100

AC:

417

AN:

41566

American (AMR)

AF:

0.0374

AC:

572

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0527

AC:

183

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.0145

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0197

AC:

209

AN:

10624

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0498

AC:

3387

AN:

68012

Other (OTH)

AF:

0.0402

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

256

512

767

1023

1279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0407

Hom.:

Bravo

AF:

0.0337

Asia WGS

AF:

0.00895

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.14

(source)

DANN

Benign

0.38

PhyloP100

-2.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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