ENST00000371929.7:c.3543delG

Variant names:

• chr9-133455575-CG-C
• rs1060499780
• ENST00000371929.7:c.3543delG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000371929.7(ADAMTS13):​c.3543delG​(p.Gln1183ArgfsTer43) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,584 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ADAMTS13 ENST00000371929.7 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -1.94

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-133455575-CG-C is Pathogenic according to our data. Variant chr9-133455575-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402223.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6	c.3400+143delG		intron_variant	Intron 25 of 28	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.3400+143delG		intron_variant	Intron 25 of 28	1	NM_139027.6	ENSP00000347927.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453584 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723346

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Upshaw-Schulman syndrome Pathogenic:1

Dec 04, 2015

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3541delG (p.Gln1183Argfs*43) frameshift variant in the ADAMTS13 gene is a novel variant and has not been previously reported. This c.3541delG variant is predicted to cause premature protein termination in exon 26 (out of a total of 29 exons in the coding sequence). Frameshift variants resulting in premature termination codons have been described in the ADAMTS13 gene in several affected individuals, including a single base-pair duplication of thymine (T) (c.3770dupT) (exon 27) (Levi et al., 2001) as well as a duplication of adenine (A), c.4143dupA (exon 29) (Schneppenheim et al., 2003) that are both predicted to result in protein truncation further down-stream from c.3541delG. This suggests that loss of function is a mechanism of disease. The c.3541delG variant has not been reported in the three control population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAC). Therefore, this collective evidence supports the classification of the c.3541delG (p.Gln1183Argfs*43) as a recessive likely pathogenic variant for congenital TPP. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060499780; hg19: chr9-136320697;