rs36221472

Variant names:

• chr9-133444950-T-C
• rs36221472
• NM_139027.6:c.2508T>C

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.2508T>C​(p.Asp836Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,613,472 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (42 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (50 hom.)
• Consequence: ADAMTS13 NM_139027.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0180
• Publications: 1 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 (MetaRNN=0.0026714504).
• BP6: Variant 9-133444950-T-C is Benign according to our data. Variant chr9-133444950-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.018 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0131 (1995/152300) while in subpopulation AFR AF = 0.0455 (1891/41570). AF 95% confidence interval is 0.0438. There are 42 homozygotes in GnomAd4. There are 948 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 42 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.2508T>C	p.Asp836Asp	synonymous	Exon 20 of 29	NP_620596.2	Q76LX8-2
	ADAMTS13	NM_139025.5		c.2508T>C	p.Asp836Asp	synonymous	Exon 20 of 29	NP_620594.1	Q76LX8-1
	ADAMTS13	NM_139026.6		c.2415T>C	p.Asp805Asp	synonymous	Exon 20 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.2508T>C	p.Asp836Asp	synonymous	Exon 20 of 29	ENSP00000347927.2	Q76LX8-2
	ADAMTS13	ENST00000371929.7	TSL:1	c.2508T>C	p.Asp836Asp	synonymous	Exon 20 of 29	ENSP00000360997.3	Q76LX8-1
	ADAMTS13	ENST00000356589.6	TSL:1	c.2415T>C	p.Asp805Asp	synonymous	Exon 20 of 29	ENSP00000348997.2	Q76LX8-3

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1991 AN: 152182 Hom.: 42 Cov.: 33

Gnomad AFR AF: 0.0455

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00346 AC: 866 AN: 250480 AF XY: 0.00240

Gnomad AFR exome AF: 0.0454

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00132 AC: 1925 AN: 1461172 Hom.: 50 Cov.: 32 AF XY: 0.00113 AC XY: 824 AN XY: 726898

African (AFR) AF: 0.0444 AC: 1488 AN: 33478

American (AMR) AF: 0.00313 AC: 140 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52718

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.000101 AC: 112 AN: 1112006

Other (OTH) AF: 0.00260 AC: 157 AN: 60388

GnomAD4 genome AF: 0.0131 AC: 1995 AN: 152300 Hom.: 42 Cov.: 33 AF XY: 0.0127 AC XY: 948 AN XY: 74468

African (AFR) AF: 0.0455 AC: 1891 AN: 41570

American (AMR) AF: 0.00431 AC: 66 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68018

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00630 Hom.: 10

Bravo AF: 0.0146

ESP6500AA AF: 0.0438 AC: 193

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00428 AC: 520

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000356

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
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.27
DANN	Benign	0.45
DEOGEN2	Benign	0.0048	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.018
Sift4G	Pathogenic	0.0	D
Vest4		0.23
MVP		0.39
ClinPred		0.0032	T
GERP RS		-3.2
Mutation Taster		=100/0	polymorphism

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: rs36221472; hg19: chr9-136310071;