rs3094374

Variant names:

• chr9-133458126-T-C
• rs3094374
• NM_139027.6:c.3909+32T>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.3909+32T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0783 in 1,608,938 control chromosomes in the GnomAD database, including 5,620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (364 hom., cov: 32)
  • Exomes 𝑓: 0.080 (5256 hom.)
• Consequence: ADAMTS13 NM_139027.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0700
• Publications: 6 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=-0.9).
• BP6: Variant 9-133458126-T-C is Benign according to our data. Variant chr9-133458126-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 262449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6	c.3909+32T>C		intron_variant	Intron 28 of 28	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.3909+32T>C		intron_variant	Intron 28 of 28	1	NM_139027.6	ENSP00000347927.2

Frequencies

GnomAD3 genomes AF: 0.0597 AC: 9088 AN: 152174 Hom.: 365 Cov.: 32

Gnomad AFR AF: 0.0172

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0567

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.0836

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0902

Gnomad OTH AF: 0.0733

GnomAD2 exomes AF: 0.0613 AC: 14805 AN: 241340 AF XY: 0.0625

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.0402

Gnomad ASJ exome AF: 0.0468

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.0930

Gnomad NFE exome AF: 0.0886

Gnomad OTH exome AF: 0.0782

GnomAD4 exome AF: 0.0803 AC: 116943 AN: 1456646 Hom.: 5256 Cov.: 32 AF XY: 0.0791 AC XY: 57319 AN XY: 724362

African (AFR) AF: 0.0140 AC: 468 AN: 33374

American (AMR) AF: 0.0413 AC: 1828 AN: 44224

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 1166 AN: 26056

East Asian (EAS) AF: 0.000253 AC: 10 AN: 39540

South Asian (SAS) AF: 0.0269 AC: 2311 AN: 85754

European-Finnish (FIN) AF: 0.0905 AC: 4722 AN: 52152

Middle Eastern (MID) AF: 0.0780 AC: 408 AN: 5234

European-Non Finnish (NFE) AF: 0.0914 AC: 101508 AN: 1110170

Other (OTH) AF: 0.0752 AC: 4522 AN: 60142

GnomAD4 genome AF: 0.0597 AC: 9088 AN: 152292 Hom.: 364 Cov.: 32 AF XY: 0.0586 AC XY: 4364 AN XY: 74466

African (AFR) AF: 0.0172 AC: 715 AN: 41572

American (AMR) AF: 0.0566 AC: 867 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0412 AC: 143 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.0236 AC: 114 AN: 4830

European-Finnish (FIN) AF: 0.0836 AC: 887 AN: 10610

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0902 AC: 6133 AN: 68002

Other (OTH) AF: 0.0720 AC: 152 AN: 2110

Alfa AF: 0.0536 Hom.: 99

Bravo AF: 0.0558

Asia WGS AF: 0.0150 AC: 53 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 17, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25242241) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely 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	-0.90
CADD	Benign	5.8
DANN	Benign	0.63
PhyloP100		-0.070
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3094374; hg19: chr9-136323248; COSMIC: COSV52470014; COSMIC: COSV52470014;