NM_139027.6:c.2910C>T

Variant names:

• chr9-133449831-C-T
• rs28641026
• NM_139027.6:c.2910C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_139027.6(ADAMTS13):​c.2910C>T​(p.Val970Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0369 in 1,613,948 control chromosomes in the GnomAD database, including 1,344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (104 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1240 hom.)
• Consequence: ADAMTS13 NM_139027.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -5.14
• Publications: 10 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 9-133449831-C-T is Benign according to our data. Variant chr9-133449831-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.14 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0308 (4694/152198) while in subpopulation NFE AF = 0.0403 (2742/67996). AF 95% confidence interval is 0.0391. There are 104 homozygotes in GnomAd4. There are 2366 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 104 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS13	NM_139027.6	MANE Select	c.2910C>T	p.Val970Val	synonymous	Exon 23 of 29	NP_620596.2	Q76LX8-2
	ADAMTS13	NM_139025.5		c.2910C>T	p.Val970Val	synonymous	Exon 23 of 29	NP_620594.1	Q76LX8-1
	ADAMTS13	NM_139026.6		c.2817C>T	p.Val939Val	synonymous	Exon 23 of 29	NP_620595.1	Q76LX8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS13	ENST00000355699.7	TSL:1 MANE Select	c.2910C>T	p.Val970Val	synonymous	Exon 23 of 29	ENSP00000347927.2	Q76LX8-2
	ADAMTS13	ENST00000371929.7	TSL:1	c.2910C>T	p.Val970Val	synonymous	Exon 23 of 29	ENSP00000360997.3	Q76LX8-1
	ADAMTS13	ENST00000356589.6	TSL:1	c.2817C>T	p.Val939Val	synonymous	Exon 23 of 29	ENSP00000348997.2	Q76LX8-3

Frequencies

GnomAD3 genomes AF: 0.0309 AC: 4692 AN: 152080 Hom.: 104 Cov.: 32

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.0723

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0403

Gnomad OTH AF: 0.0283

GnomAD2 exomes AF: 0.0313 AC: 7850 AN: 250634 AF XY: 0.0324

Gnomad AFR exome AF: 0.0100

Gnomad AMR exome AF: 0.0150

Gnomad ASJ exome AF: 0.0227

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.0675

Gnomad NFE exome AF: 0.0405

Gnomad OTH exome AF: 0.0335

GnomAD4 exome AF: 0.0376 AC: 54923 AN: 1461750 Hom.: 1240 Cov.: 32 AF XY: 0.0372 AC XY: 27065 AN XY: 727178

African (AFR) AF: 0.00980 AC: 328 AN: 33480

American (AMR) AF: 0.0149 AC: 667 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 581 AN: 26134

East Asian (EAS) AF: 0.000327 AC: 13 AN: 39700

South Asian (SAS) AF: 0.0229 AC: 1979 AN: 86252

European-Finnish (FIN) AF: 0.0660 AC: 3520 AN: 53316

Middle Eastern (MID) AF: 0.0333 AC: 192 AN: 5758

European-Non Finnish (NFE) AF: 0.0411 AC: 45684 AN: 1112002

Other (OTH) AF: 0.0324 AC: 1959 AN: 60390

GnomAD4 genome AF: 0.0308 AC: 4694 AN: 152198 Hom.: 104 Cov.: 32 AF XY: 0.0318 AC XY: 2366 AN XY: 74400

African (AFR) AF: 0.0117 AC: 488 AN: 41542

American (AMR) AF: 0.0226 AC: 345 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.0186 AC: 90 AN: 4826

European-Finnish (FIN) AF: 0.0723 AC: 766 AN: 10588

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

European-Non Finnish (NFE) AF: 0.0403 AC: 2742 AN: 67996

Other (OTH) AF: 0.0280 AC: 59 AN: 2110

Alfa AF: 0.0311 Hom.: 50

Bravo AF: 0.0258

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.0379

EpiControl AF: 0.0370

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Upshaw-Schulman syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.27
DANN	Benign	0.79
PhyloP100		-5.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs28641026; hg19: chr9-136314952;