rs36222275

Positions:

chr9-133449865-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

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. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 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 id is 1590075.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS13	NM_139027.6 linkuse as main transcript	c.2944G>A	p.Gly982Arg	missense_variant	23/29	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7 linkuse as main transcript	c.2944G>A	p.Gly982Arg	missense_variant	23/29	1	NM_139027.6	ENSP00000347927	A2	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

GnomAD3 exomes

AF:

0.00109

AC:

274

AN:

250462

Hom.:

AF XY:

0.00113

AC XY:

153

AN XY:

135700

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 SAS 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

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00161

Gnomad4 NFE exome

AF:

0.00179

Gnomad4 OTH exome

AF:

0.00132

GnomAD4 genome

AF:

0.00114

AC:

173

AN:

152328

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00301

Gnomad4 NFE

AF:

0.00184

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00165

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

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 13, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 17, 2022

- -

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

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;.

MutationTaster

Benign

1.0

N;N;N;N;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over