9-133439340-A-G

Variant names:

• chr9-133439340-A-G
• rs75039118
• NM_139027.6:c.1706-26A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_139027.6(ADAMTS13):​c.1706-26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000596 in 1,480,452 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00090 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (4 hom.)
• Consequence: ADAMTS13 NM_139027.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.516
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0009 (137/152304) while in subpopulation EAS AF = 0.0199 (103/5188). AF 95% confidence interval is 0.0167. There are 3 homozygotes in GnomAd4. There are 81 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139027.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS13	NM_139027.6	MANE Select	c.1706-26A>G		intron	N/A	NP_620596.2
	ADAMTS13	NM_139025.5		c.1706-26A>G		intron	N/A	NP_620594.1
	ADAMTS13	NM_139026.6		c.1613-26A>G		intron	N/A	NP_620595.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS13	ENST00000355699.7	TSL:1 MANE Select	c.1706-26A>G		intron	N/A	ENSP00000347927.2
	ADAMTS13	ENST00000371929.7	TSL:1	c.1706-26A>G		intron	N/A	ENSP00000360997.3
	ADAMTS13	ENST00000356589.6	TSL:1	c.1613-26A>G		intron	N/A	ENSP00000348997.2

Frequencies

GnomAD3 genomes AF: 0.000907 AC: 138 AN: 152186 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0200

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00172 AC: 432 AN: 251350 AF XY: 0.00160

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0202

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000562 AC: 746 AN: 1328148 Hom.: 4 Cov.: 24 AF XY: 0.000510 AC XY: 341 AN XY: 668500

African (AFR) AF: 0.0000968 AC: 3 AN: 31004

American (AMR) AF: 0.0000449 AC: 2 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25206

East Asian (EAS) AF: 0.0126 AC: 488 AN: 38788

South Asian (SAS) AF: 0.000348 AC: 29 AN: 83272

European-Finnish (FIN) AF: 0.00150 AC: 80 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5492

European-Non Finnish (NFE) AF: 0.0000626 AC: 62 AN: 990748

Other (OTH) AF: 0.00147 AC: 82 AN: 55762

GnomAD4 genome AF: 0.000900 AC: 137 AN: 152304 Hom.: 3 Cov.: 33 AF XY: 0.00109 AC XY: 81 AN XY: 74456

African (AFR) AF: 0.000120 AC: 5 AN: 41562

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0199 AC: 103 AN: 5188

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4832

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00126 Hom.: 0

Bravo AF: 0.000918

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.71
DANN	Benign	0.37
PhyloP100		0.52
Mutation Taster		=100/0	polymorphism

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: rs75039118; hg19: chr9-136304461;