rs36218903

Variant names:

• chr9-133426166-G-A
• rs36218903
• NM_139027.6:c.540-33G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_139027.6(ADAMTS13):​c.540-33G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 1,613,958 control chromosomes in the GnomAD database, including 220 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (11 hom., cov: 33)
  • Exomes 𝑓: 0.016 (209 hom.)
• Consequence: ADAMTS13 NM_139027.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0700
• Publications: 2 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=-0.81).
• BP6: Variant 9-133426166-G-A is Benign according to our data. Variant chr9-133426166-G-A is described in ClinVar as Benign. ClinVar VariationId is 262451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0104 (1585/152340) while in subpopulation NFE AF = 0.0176 (1196/68024). AF 95% confidence interval is 0.0168. There are 11 homozygotes in GnomAd4. There are 721 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6	c.540-33G>A		intron_variant	Intron 5 of 28	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.540-33G>A		intron_variant	Intron 5 of 28	1	NM_139027.6	ENSP00000347927.2

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1582 AN: 152222 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00798

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0176

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0111 AC: 2800 AN: 251168 AF XY: 0.0114

Gnomad AFR exome AF: 0.00302

Gnomad AMR exome AF: 0.00682

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00520

Gnomad NFE exome AF: 0.0178

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0156 AC: 22789 AN: 1461618 Hom.: 209 Cov.: 36 AF XY: 0.0154 AC XY: 11215 AN XY: 727128

African (AFR) AF: 0.00272 AC: 91 AN: 33480

American (AMR) AF: 0.00724 AC: 324 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0126 AC: 330 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00558 AC: 481 AN: 86258

European-Finnish (FIN) AF: 0.00679 AC: 361 AN: 53162

Middle Eastern (MID) AF: 0.0133 AC: 77 AN: 5768

European-Non Finnish (NFE) AF: 0.0183 AC: 20337 AN: 1112002

Other (OTH) AF: 0.0130 AC: 786 AN: 60388

GnomAD4 genome AF: 0.0104 AC: 1585 AN: 152340 Hom.: 11 Cov.: 33 AF XY: 0.00968 AC XY: 721 AN XY: 74504

African (AFR) AF: 0.00313 AC: 130 AN: 41592

American (AMR) AF: 0.00810 AC: 124 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4828

European-Finnish (FIN) AF: 0.00395 AC: 42 AN: 10622

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0176 AC: 1196 AN: 68024

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.0130 Hom.: 2

Bravo AF: 0.0103

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.4
DANN	Benign	0.77
PhyloP100		0.070
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs36218903; hg19: chr9-136291286;