rs36222275

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_139027.6(ADAMTS13):c.2944G>A(p.Gly982Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,614,086 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 2 hom. )

Consequence

ADAMTS13
NM_139027.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 1.14

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 -9 ACMG points.

BP6

Variant 9-133449865-G-A is Benign according to our data. Variant chr9-133449865-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1590075.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00114 (173/152328) while in subpopulation NFE AF = 0.00184 (125/68016). AF 95% confidence interval is 0.00158. There are 0 homozygotes in GnomAd4. There are 86 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6 link	c.2944G>A	p.Gly982Arg	missense_variant	Exon 23 of 29	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.2944G>A	p.Gly982Arg	missense_variant	Exon 23 of 29	1	NM_139027.6	ENSP00000347927.2		Q76LX8-2

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

173

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00301

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00184

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00109

AC:

274

AN:

250462

AF XY:

0.00113

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00199

Gnomad NFE exome

AF:

0.00186

Gnomad OTH exome

AF:

0.000819

GnomAD4 exome

AF:

0.00150

AC:

2190

AN:

1461758

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

1060

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33478

American (AMR)

AF:

0.000425

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00161

AC:

AN:

53344

Middle Eastern (MID)

AF:

0.000697

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00179

AC:

1986

AN:

1112008

Other (OTH)

AF:

0.00132

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

126

252

378

504

630

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<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:

0.00114

AC:

173

AN:

152328

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41588

American (AMR)

AF:

0.000196

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00301

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00184

AC:

125

AN:

68016

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00154

Hom.:

Bravo

AF:

0.000835

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.000964

AC:

117

EpiCase

AF:

0.00169

EpiControl

AF:

0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

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

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Mar 13, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ADAMTS13 c.2944G>A (p.Gly982Arg) results in a non-conservative amino acid change located in the Thrombospondin type-1 (TSP1) repeat (IPR000884) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 250462 control chromosomes, predominantly at a frequency of 0.0019 within the Non-Finnish European subpopulation in the gnomAD database. c.2944G>A has been reported in the literature in individuals with suspected inherited bleeding disorders (Leinoe_2017). This report does not provide unequivocal conclusions about association of the variant with Thrombotic Thrombocytopenic Purpura. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28748566, 27802307). ClinVar contains an entry for this variant (Variation ID: 1590075). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Upshaw-Schulman syndrome

Uncertain:1

Mar 17, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;.;.

Eigen

Benign

-0.094

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.73

T;T;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

2.0

M;M;.

PhyloP100

1.1

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.0

N;N;N

REVEL

Benign

0.16

Sift

Benign

0.15

T;D;D

Sift4G

Benign

0.079

T;T;.

Polyphen

0.99

D;D;D

Vest4

0.45

MutPred

0.22

Gain of MoRF binding (P = 0.0644);Gain of MoRF binding (P = 0.0644);.;

MVP

0.77

MPC

0.61

ClinPred

0.013

GERP RS

3.1

Varity_R

0.11

gMVP

0.44

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.47

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.47

Position offset: 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