Genetic Variant ADAMTS13:p.Asp235Tyr (chr9-133428650-G-T) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_139027.6(ADAMTS13):c.703G>T(p.Asp235Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000228 in 1,315,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D235H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Consequence

ADAMTS13
NM_139027.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 7.40

Publications

6 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_139027.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-133428650-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 68827.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 9-133428650-G-T is Pathogenic according to our data. Variant chr9-133428650-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2136831.

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.703G>T	p.Asp235Tyr	missense	Exon 7 of 29	NP_620596.2	Q76LX8-2
ADAMTS13	NM_139025.5		c.703G>T	p.Asp235Tyr	missense	Exon 7 of 29	NP_620594.1	Q76LX8-1
ADAMTS13	NM_139026.6		c.703G>T	p.Asp235Tyr	missense	Exon 7 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.703G>T	p.Asp235Tyr	missense	Exon 7 of 29	ENSP00000347927.2	Q76LX8-2
ADAMTS13	ENST00000371929.7	TSL:1	c.703G>T	p.Asp235Tyr	missense	Exon 7 of 29	ENSP00000360997.3	Q76LX8-1
ADAMTS13	ENST00000356589.6	TSL:1	c.703G>T	p.Asp235Tyr	missense	Exon 7 of 29	ENSP00000348997.2	Q76LX8-3

Frequencies

GnomAD3 genomes

AF:

0.00000682

AC:

AN:

146638

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000150

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000151

AC:

AN:

66246

AF XY:

0.0000257

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000403

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000171

AC:

AN:

1169112

Hom.:

Cov.:

AF XY:

0.00000350

AC XY:

AN XY:

572234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23512

American (AMR)

AF:

0.00

AC:

AN:

19646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18440

East Asian (EAS)

AF:

0.00

AC:

AN:

22240

South Asian (SAS)

AF:

0.0000187

AC:

AN:

53518

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24200

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3184

European-Non Finnish (NFE)

AF:

0.00000104

AC:

AN:

958670

Other (OTH)

AF:

0.00

AC:

AN:

45702

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000682

AC:

AN:

146638

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71278

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

40226

American (AMR)

AF:

0.00

AC:

AN:

14566

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3414

East Asian (EAS)

AF:

0.00

AC:

AN:

4708

South Asian (SAS)

AF:

0.00

AC:

AN:

4474

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000150

AC:

AN:

66598

Other (OTH)

AF:

0.00

AC:

AN:

2038

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Upshaw-Schulman syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.6

PhyloP100

7.4

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-8.1

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.86

MutPred

0.80

Loss of disorder (P = 0.0429)

MVP

0.96

MPC

1.2

ClinPred

1.0

GERP RS

3.5

Varity_R

0.91

gMVP

0.96

Mutation Taster

=1/99

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over