rs652600

Variant names:

• chr9-133445896-G-A
• rs652600
• NM_139027.6:c.2731+77G>A

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.2731+77G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.681 in 1,500,210 control chromosomes in the GnomAD database, including 355,034 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33504 hom., cov: 32)
  • Exomes 𝑓: 0.68 (321530 hom.)
• Consequence: ADAMTS13 NM_139027.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.247
• Publications: 21 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=-0.91).
• BP6: Variant 9-133445896-G-A is Benign according to our data. Variant chr9-133445896-G-A is described in ClinVar as Benign. ClinVar VariationId is 812619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6	c.2731+77G>A		intron_variant	Intron 21 of 28	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.2731+77G>A		intron_variant	Intron 21 of 28	1	NM_139027.6	ENSP00000347927.2

Frequencies

GnomAD3 genomes AF: 0.653 AC: 99240 AN: 151968 Hom.: 33468 Cov.: 32

Gnomad AFR AF: 0.592

Gnomad AMI AF: 0.823

Gnomad AMR AF: 0.602

Gnomad ASJ AF: 0.621

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.600

Gnomad FIN AF: 0.810

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.642

GnomAD4 exome AF: 0.684 AC: 921726 AN: 1348124 Hom.: 321530 AF XY: 0.682 AC XY: 449389 AN XY: 658514

African (AFR) AF: 0.585 AC: 17538 AN: 29966

American (AMR) AF: 0.597 AC: 16871 AN: 28258

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 11973 AN: 19812

East Asian (EAS) AF: 0.200 AC: 7580 AN: 37860

South Asian (SAS) AF: 0.613 AC: 42638 AN: 69512

European-Finnish (FIN) AF: 0.808 AC: 36447 AN: 45108

Middle Eastern (MID) AF: 0.620 AC: 3251 AN: 5246

European-Non Finnish (NFE) AF: 0.709 AC: 749146 AN: 1056832

Other (OTH) AF: 0.653 AC: 36282 AN: 55530

GnomAD4 genome AF: 0.653 AC: 99318 AN: 152086 Hom.: 33504 Cov.: 32 AF XY: 0.653 AC XY: 48521 AN XY: 74350

African (AFR) AF: 0.592 AC: 24562 AN: 41470

American (AMR) AF: 0.602 AC: 9193 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.621 AC: 2154 AN: 3468

East Asian (EAS) AF: 0.207 AC: 1067 AN: 5164

South Asian (SAS) AF: 0.601 AC: 2898 AN: 4820

European-Finnish (FIN) AF: 0.810 AC: 8584 AN: 10600

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.715 AC: 48591 AN: 67972

Other (OTH) AF: 0.637 AC: 1348 AN: 2116

Alfa AF: 0.669 Hom.: 46761

Bravo AF: 0.629

Asia WGS AF: 0.450 AC: 1568 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Three Vessel Coronary Disease Benign:1

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Department of Cardiology, Chinese Academy of Medical Sciences, Fuwai Hospital

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.081
DANN	Benign	0.66
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs652600; hg19: chr9-136311017; COSMIC: COSV63021038;