Genetic Variant ADAMTS13:p.Val1226Val (chr9-133456673-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_139027.6(ADAMTS13):c.3678G>A(p.Val1226Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,593,784 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0077 ( 11 hom., cov: 33)

Exomes 𝑓: 0.00080 ( 18 hom. )

Consequence

ADAMTS13
NM_139027.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.144

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 9-133456673-G-A is Benign according to our data. Variant chr9-133456673-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.144 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00771 (1174/152308) while in subpopulation AFR AF = 0.0265 (1103/41554). AF 95% confidence interval is 0.0252. There are 11 homozygotes in GnomAd4. There are 559 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADAMTS13	NM_139027.6	MANE Select	c.3678G>A	p.Val1226Val	synonymous	Exon 27 of 29	NP_620596.2
ADAMTS13	NM_139025.5		c.3846G>A	p.Val1282Val	synonymous	Exon 27 of 29	NP_620594.1
ADAMTS13	NM_139026.6		c.3585G>A	p.Val1195Val	synonymous	Exon 27 of 29	NP_620595.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADAMTS13	ENST00000355699.7	TSL:1 MANE Select	c.3678G>A	p.Val1226Val	synonymous	Exon 27 of 29	ENSP00000347927.2
ADAMTS13	ENST00000371929.7	TSL:1	c.3846G>A	p.Val1282Val	synonymous	Exon 27 of 29	ENSP00000360997.3
ADAMTS13	ENST00000356589.6	TSL:1	c.3585G>A	p.Val1195Val	synonymous	Exon 27 of 29	ENSP00000348997.2

Frequencies

GnomAD3 genomes

AF:

0.00770

AC:

1172

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00353

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00200

AC:

426

AN:

212620

AF XY:

0.00139

show subpopulations

Gnomad AFR exome

AF:

0.0279

Gnomad AMR exome

AF:

0.00173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000537

Gnomad OTH exome

AF:

0.00110

GnomAD4 exome

AF:

0.000796

AC:

1147

AN:

1441476

Hom.:

Cov.:

AF XY:

0.000693

AC XY:

496

AN XY:

715358

show subpopulations

African (AFR)

AF:

0.0276

AC:

917

AN:

33214

American (AMR)

AF:

0.00170

AC:

AN:

41244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25698

East Asian (EAS)

AF:

0.00

AC:

AN:

39068

South Asian (SAS)

AF:

0.0000239

AC:

AN:

83638

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51756

Middle Eastern (MID)

AF:

0.00262

AC:

AN:

5338

European-Non Finnish (NFE)

AF:

0.0000436

AC:

AN:

1101960

Other (OTH)

AF:

0.00161

AC:

AN:

59560

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

130

196

261

326

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00771

AC:

1174

AN:

152308

Hom.:

Cov.:

AF XY:

0.00751

AC XY:

559

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0265

AC:

1103

AN:

41554

American (AMR)

AF:

0.00353

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68026

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

120

179

239

299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00414

Hom.:

Bravo

AF:

0.00906

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

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

-0.74

CADD

Benign

2.6

(source)

DANN

Benign

0.62

PhyloP100

-0.14

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over