rs2301611

Variant names:

• chr9-133425487-T-C
• rs2301611
• NM_139027.6:c.331-42T>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.331-42T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,578,718 control chromosomes in the GnomAD database, including 1,127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (161 hom., cov: 32)
  • Exomes 𝑓: 0.012 (966 hom.)
• Consequence: ADAMTS13 NM_139027.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0910
• Publications: 5 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=-0.88).
• BP6: Variant 9-133425487-T-C is Benign according to our data. Variant chr9-133425487-T-C is described in ClinVar as Benign. ClinVar VariationId is 1268106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6	c.331-42T>C		intron_variant	Intron 3 of 28	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.331-42T>C		intron_variant	Intron 3 of 28	1	NM_139027.6	ENSP00000347927.2

Frequencies

GnomAD3 genomes AF: 0.0280 AC: 4251 AN: 152012 Hom.: 160 Cov.: 32

Gnomad AFR AF: 0.0630

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0185

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00422

Gnomad OTH AF: 0.0216

GnomAD2 exomes AF: 0.0227 AC: 4748 AN: 209148 AF XY: 0.0206

Gnomad AFR exome AF: 0.0634

Gnomad AMR exome AF: 0.0283

Gnomad ASJ exome AF: 0.0166

Gnomad EAS exome AF: 0.133

Gnomad FIN exome AF: 0.00893

Gnomad NFE exome AF: 0.00354

Gnomad OTH exome AF: 0.0164

GnomAD4 exome AF: 0.0120 AC: 17060 AN: 1426588 Hom.: 966 Cov.: 29 AF XY: 0.0119 AC XY: 8413 AN XY: 708218

African (AFR) AF: 0.0647 AC: 2116 AN: 32728

American (AMR) AF: 0.0260 AC: 1059 AN: 40734

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 470 AN: 25500

East Asian (EAS) AF: 0.199 AC: 7624 AN: 38262

South Asian (SAS) AF: 0.0126 AC: 1040 AN: 82530

European-Finnish (FIN) AF: 0.00732 AC: 372 AN: 50792

Middle Eastern (MID) AF: 0.0251 AC: 125 AN: 4972

European-Non Finnish (NFE) AF: 0.00292 AC: 3191 AN: 1091990

Other (OTH) AF: 0.0180 AC: 1063 AN: 59080

GnomAD4 genome AF: 0.0280 AC: 4259 AN: 152130 Hom.: 161 Cov.: 32 AF XY: 0.0286 AC XY: 2126 AN XY: 74344

African (AFR) AF: 0.0629 AC: 2610 AN: 41502

American (AMR) AF: 0.0184 AC: 282 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 63 AN: 3470

East Asian (EAS) AF: 0.144 AC: 740 AN: 5148

South Asian (SAS) AF: 0.0175 AC: 84 AN: 4810

European-Finnish (FIN) AF: 0.0127 AC: 134 AN: 10590

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00422 AC: 287 AN: 68002

Other (OTH) AF: 0.0251 AC: 53 AN: 2110

Alfa AF: 0.0195 Hom.: 15

Bravo AF: 0.0310

Asia WGS AF: 0.0800 AC: 279 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	-0.88
CADD	Benign	5.2
DANN	Benign	0.72
PhyloP100		0.091
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: rs2301611; hg19: chr9-136290607; COSMIC: COSV63021255;