Genetic Variant ADAMTS13:c.173-48G>A (chr9-133424273-G-A) – 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.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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.32

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 links:

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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=-0.97).

BP6

Variant 9-133424273-G-A is Benign according to our data. Variant chr9-133424273-G-A is described in ClinVar as [Benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6 link	c.173-48G>A		intron_variant	Intron 2 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.173-48G>A		intron_variant	Intron 2 of 28	1	NM_139027.6	ENSP00000347927.2		Q76LX8-2

Frequencies

GnomAD3 genomes

AF:

0.0548

AC:

8334

AN:

152002

Hom.:

326

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0724

AC XY:

52397

AN XY:

723446

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

5083

10166

15248

20331

25414

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0548

AC:

8330

AN:

152120

Hom.:

325

Cov.:

AF XY:

0.0535

AC XY:

3975

AN XY:

74346

show subpopulations

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:

AN:

5134

South Asian (SAS)

AF:

0.0197

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0547

AC:

580

AN:

10598

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0866

AC:

5888

AN:

67994

Other (OTH)

AF:

0.0546

AC:

115

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

422

845

1267

1690

2112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0741

Hom.:

143

Bravo

AF:

0.0534

Asia WGS

AF:

0.0150

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 18, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.013

(source)

DANN

Benign

0.67

PhyloP100

-2.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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chr9-133424273-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over