Genetic Variant NM_139027.6:c.1245-32C>G (chr9-133433609-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_139027.6(ADAMTS13):c.1245-32C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.555 in 1,613,598 control chromosomes in the GnomAD database, including 254,935 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.56 ( 25075 hom., cov: 32)

Exomes 𝑓: 0.55 ( 229860 hom. )

Consequence

ADAMTS13
NM_139027.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.01

Publications

17 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6 link	c.1245-32C>G		intron_variant	Intron 10 of 28	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.1245-32C>G		intron_variant	Intron 10 of 28	1	NM_139027.6	ENSP00000347927.2		Q76LX8-2

Frequencies

GnomAD3 genomes

AF:

0.565

AC:

85785

AN:

151890

Hom.:

25040

Cov.:

show subpopulations

Gnomad AFR

AF:

0.640

Gnomad AMI

AF:

0.438

Gnomad AMR

AF:

0.503

Gnomad ASJ

AF:

0.371

Gnomad EAS

AF:

0.192

Gnomad SAS

AF:

0.464

Gnomad FIN

AF:

0.633

Gnomad MID

AF:

0.420

Gnomad NFE

AF:

0.571

Gnomad OTH

AF:

0.523

GnomAD4 exome

AF:

0.554

AC:

810345

AN:

1461590

Hom.:

229860

Cov.:

AF XY:

0.552

AC XY:

401183

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.644

AC:

21550

AN:

33480

American (AMR)

AF:

0.503

AC:

22487

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.373

AC:

9741

AN:

26132

East Asian (EAS)

AF:

0.190

AC:

7556

AN:

39694

South Asian (SAS)

AF:

0.479

AC:

41287

AN:

86256

European-Finnish (FIN)

AF:

0.642

AC:

34185

AN:

53262

Middle Eastern (MID)

AF:

0.465

AC:

2677

AN:

5756

European-Non Finnish (NFE)

AF:

0.575

AC:

638799

AN:

1111918

Other (OTH)

AF:

0.531

AC:

32063

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

24757

49514

74272

99029

123786

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17492

34984

52476

69968

87460

<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:

0.565

AC:

85864

AN:

152008

Hom.:

25075

Cov.:

AF XY:

0.564

AC XY:

41926

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.640

AC:

26522

AN:

41432

American (AMR)

AF:

0.503

AC:

7678

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.371

AC:

1288

AN:

3468

East Asian (EAS)

AF:

0.192

AC:

991

AN:

5166

South Asian (SAS)

AF:

0.466

AC:

2244

AN:

4818

European-Finnish (FIN)

AF:

0.633

AC:

6701

AN:

10592

Middle Eastern (MID)

AF:

0.435

AC:

127

AN:

292

European-Non Finnish (NFE)

AF:

0.571

AC:

38821

AN:

67946

Other (OTH)

AF:

0.519

AC:

1093

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1869

3738

5606

7475

9344

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

724

1448

2172

2896

3620

<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:

0.506

Hom.:

3190

Bravo

AF:

0.553

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.68

(source)

PhyloP100

-1.0

Splicing

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

Computational scores

Splicing

Publications

Other links and lift over