NM_139027.6:c.1874G>A

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.1874G>A(p.Arg625His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,613,770 control chromosomes in the GnomAD database, including 195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R625C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.020 ( 113 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 82 hom. )

Consequence

ADAMTS13
NM_139027.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.92

Publications

10 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 (MetaRNN=0.00303033).

BP6

Variant 9-133440431-G-A is Benign according to our data. Variant chr9-133440431-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0681 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAMTS13	NM_139027.6	MANE Select	c.1874G>A	p.Arg625His	missense	Exon 16 of 29	NP_620596.2	Q76LX8-2
ADAMTS13	NM_139025.5		c.1874G>A	p.Arg625His	missense	Exon 16 of 29	NP_620594.1	Q76LX8-1
ADAMTS13	NM_139026.6		c.1781G>A	p.Arg594His	missense	Exon 16 of 29	NP_620595.1	Q76LX8-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAMTS13	ENST00000355699.7	TSL:1 MANE Select	c.1874G>A	p.Arg625His	missense	Exon 16 of 29	ENSP00000347927.2	Q76LX8-2
ADAMTS13	ENST00000371929.7	TSL:1	c.1874G>A	p.Arg625His	missense	Exon 16 of 29	ENSP00000360997.3	Q76LX8-1
ADAMTS13	ENST00000356589.6	TSL:1	c.1781G>A	p.Arg594His	missense	Exon 16 of 29	ENSP00000348997.2	Q76LX8-3

Frequencies

GnomAD3 genomes

AF:

0.0201

AC:

3056

AN:

152102

Hom.:

113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0702

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00674

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.0143

GnomAD2 exomes

AF:

0.00534

AC:

1341

AN:

250902

AF XY:

0.00401

show subpopulations

Gnomad AFR exome

AF:

0.0728

Gnomad AMR exome

AF:

0.00367

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00208

AC:

3035

AN:

1461550

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

1285

AN XY:

727068

show subpopulations

African (AFR)

AF:

0.0713

AC:

2386

AN:

33478

American (AMR)

AF:

0.00420

AC:

188

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000128

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53122

Middle Eastern (MID)

AF:

0.00225

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000171

AC:

190

AN:

1111978

Other (OTH)

AF:

0.00407

AC:

246

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

184

369

553

738

922

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<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:

0.0201

AC:

3064

AN:

152220

Hom.:

113

Cov.:

AF XY:

0.0190

AC XY:

1414

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0702

AC:

2915

AN:

41516

American (AMR)

AF:

0.00673

AC:

103

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68010

Other (OTH)

AF:

0.0142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

141

283

424

566

707

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00755

Hom.:

Bravo

AF:

0.0230

ESP6500AA

AF:

0.0776

AC:

342

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00698

AC:

847

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Upshaw-Schulman syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Benign

0.045

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.099

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.4

PhyloP100

1.9

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.31

Sift

Benign

0.23

Sift4G

Uncertain

0.020

Polyphen

1.0

Vest4

0.28

MVP

0.87

MPC

0.58

ClinPred

0.030

GERP RS

4.1

Varity_R

0.097

gMVP

0.55

Mutation Taster

=73/27

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Computational scores

Splicing

Publications

Other links and lift over