9-133422276-C-T

Position:

• chr9-133422276-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000371929(ADAMTS13):​c.-168C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00372 in 669,392 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (6 hom.)
• Consequence: ADAMTS13 ENST00000371929 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.02

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 9-133422276-C-T is Benign according to our data. Variant chr9-133422276-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 913693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00659 (1004/152296) while in subpopulation AFR AF= 0.0169 (703/41570). AF 95% confidence interval is 0.0159. There are 9 homozygotes in gnomad4. There are 486 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS13	XM_017014232.2	c.93+298C>T		intron_variant			XP_016869721.1
ADAMTS13	XM_017014233.2	c.-285-825C>T		intron_variant			XP_016869722.1
ADAMTS13	NR_024514.3	n.309-825C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000371929	c.-168C>T		5_prime_UTR_variant	1/29	1		ENSP00000360997.3
ADAMTS13	ENST00000485925.5	n.288-825C>T		intron_variant		1
ADAMTS13	ENST00000371916	c.-912C>T		5_prime_UTR_variant	1/26	5		ENSP00000360984.2

Frequencies

GnomAD3 genomes AF: 0.00660 AC: 1005 AN: 152178 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00185

Gnomad OTH AF: 0.00908

GnomAD4 exome AF: 0.00288 AC: 1487 AN: 517096 Hom.: 6 Cov.: 6 AF XY: 0.00280 AC XY: 762 AN XY: 272358

Gnomad4 AFR exome AF: 0.0180

Gnomad4 AMR exome AF: 0.00391

Gnomad4 ASJ exome AF: 0.0134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000774

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00198

Gnomad4 OTH exome AF: 0.00531

GnomAD4 genome AF: 0.00659 AC: 1004 AN: 152296 Hom.: 9 Cov.: 32 AF XY: 0.00653 AC XY: 486 AN XY: 74458

Gnomad4 AFR AF: 0.0169

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00185

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00569 Hom.: 0

Bravo AF: 0.00747

Asia WGS AF: 0.00231 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Upshaw-Schulman syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.0
DANN	Benign	0.59

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

LitVar

Other links and lift over

dbSNP: rs36218240; hg19: chr9-136287396;