chr9-133424254-T-C

Variant names:

• chr9-133424254-T-C
• rs2285489
• NM_139027.6:c.173-67T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_139027.6(ADAMTS13):​c.173-67T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.636 in 1,601,052 control chromosomes in the GnomAD database, including 327,527 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (35606 hom., cov: 31)
  • Exomes 𝑓: 0.63 (291921 hom.)
• Consequence: ADAMTS13 NM_139027.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.60
• Publications: 19 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 9-133424254-T-C is Benign according to our data. Variant chr9-133424254-T-C is described in ClinVar as Benign. ClinVar VariationId is 1221388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6	c.173-67T>C		intron_variant	Intron 2 of 28	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.173-67T>C		intron_variant	Intron 2 of 28	1	NM_139027.6	ENSP00000347927.2

Frequencies

GnomAD3 genomes AF: 0.679 AC: 103067 AN: 151806 Hom.: 35562 Cov.: 31

Gnomad AFR AF: 0.773

Gnomad AMI AF: 0.705

Gnomad AMR AF: 0.685

Gnomad ASJ AF: 0.770

Gnomad EAS AF: 0.845

Gnomad SAS AF: 0.567

Gnomad FIN AF: 0.560

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.627

Gnomad OTH AF: 0.716

GnomAD4 exome AF: 0.631 AC: 914860 AN: 1449128 Hom.: 291921 AF XY: 0.629 AC XY: 453762 AN XY: 721286

African (AFR) AF: 0.773 AC: 25812 AN: 33384

American (AMR) AF: 0.639 AC: 28571 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.767 AC: 20032 AN: 26120

East Asian (EAS) AF: 0.854 AC: 33877 AN: 39674

South Asian (SAS) AF: 0.564 AC: 48551 AN: 86132

European-Finnish (FIN) AF: 0.548 AC: 24222 AN: 44184

Middle Eastern (MID) AF: 0.755 AC: 3142 AN: 4164

European-Non Finnish (NFE) AF: 0.622 AC: 691170 AN: 1110660

Other (OTH) AF: 0.657 AC: 39483 AN: 60110

GnomAD4 genome AF: 0.679 AC: 103165 AN: 151924 Hom.: 35606 Cov.: 31 AF XY: 0.676 AC XY: 50188 AN XY: 74246

African (AFR) AF: 0.774 AC: 32060 AN: 41438

American (AMR) AF: 0.685 AC: 10463 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.770 AC: 2673 AN: 3470

East Asian (EAS) AF: 0.846 AC: 4336 AN: 5126

South Asian (SAS) AF: 0.566 AC: 2721 AN: 4806

European-Finnish (FIN) AF: 0.560 AC: 5921 AN: 10570

Middle Eastern (MID) AF: 0.789 AC: 232 AN: 294

European-Non Finnish (NFE) AF: 0.627 AC: 42608 AN: 67924

Other (OTH) AF: 0.717 AC: 1511 AN: 2106

Alfa AF: 0.648 Hom.: 4523

Bravo AF: 0.699

Asia WGS AF: 0.713 AC: 2479 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.61
DANN	Benign	0.41
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2285489; hg19: chr9-136289374; COSMIC: COSV63020635;