chr9-133445796-C-T

Variant names:

• chr9-133445796-C-T
• rs78977446
• NM_139027.6:c.2708C>T

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.2708C>T​(p.Ser903Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,590,318 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S903S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (41 hom.)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.625
• Publications: 16 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 (MetaRNN=0.012989759).
• BP6: Variant 9-133445796-C-T is Benign according to our data. Variant chr9-133445796-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 365555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00156 (238/152232) while in subpopulation EAS AF = 0.0424 (219/5162). AF 95% confidence interval is 0.0378. There are 5 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.2708C>T	p.Ser903Leu	missense	Exon 21 of 29	NP_620596.2	Q76LX8-2
	ADAMTS13	NM_139025.5		c.2708C>T	p.Ser903Leu	missense	Exon 21 of 29	NP_620594.1	Q76LX8-1
	ADAMTS13	NM_139026.6		c.2615C>T	p.Ser872Leu	missense	Exon 21 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.2708C>T	p.Ser903Leu	missense	Exon 21 of 29	ENSP00000347927.2	Q76LX8-2
	ADAMTS13	ENST00000371929.7	TSL:1	c.2708C>T	p.Ser903Leu	missense	Exon 21 of 29	ENSP00000360997.3	Q76LX8-1
	ADAMTS13	ENST00000356589.6	TSL:1	c.2615C>T	p.Ser872Leu	missense	Exon 21 of 29	ENSP00000348997.2	Q76LX8-3

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 238 AN: 152110 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0423

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00355 AC: 855 AN: 240894 AF XY: 0.00323

Gnomad AFR exome AF: 0.0000625

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0449

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000934

Gnomad OTH exome AF: 0.000509

GnomAD4 exome AF: 0.00136 AC: 1956 AN: 1438086 Hom.: 41 Cov.: 32 AF XY: 0.00133 AC XY: 946 AN XY: 710674

African (AFR) AF: 0.0000604 AC: 2 AN: 33092

American (AMR) AF: 0.0000912 AC: 4 AN: 43848

Ashkenazi Jewish (ASJ) AF: 0.0000393 AC: 1 AN: 25426

East Asian (EAS) AF: 0.0445 AC: 1740 AN: 39128

South Asian (SAS) AF: 0.000930 AC: 79 AN: 84942

European-Finnish (FIN) AF: 0.0000384 AC: 2 AN: 52134

Middle Eastern (MID) AF: 0.000352 AC: 2 AN: 5682

European-Non Finnish (NFE) AF: 0.0000265 AC: 29 AN: 1094578

Other (OTH) AF: 0.00164 AC: 97 AN: 59256

GnomAD4 genome AF: 0.00156 AC: 238 AN: 152232 Hom.: 5 Cov.: 33 AF XY: 0.00195 AC XY: 145 AN XY: 74440

African (AFR) AF: 0.0000481 AC: 2 AN: 41550

American (AMR) AF: 0.000131 AC: 2 AN: 15284

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

East Asian (EAS) AF: 0.0424 AC: 219 AN: 5162

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4820

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68004

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000388 Hom.: 0

Bravo AF: 0.00177

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00339 AC: 411

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Upshaw-Schulman syndrome (4)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.2
DANN	Benign	0.96
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.92	N
PhyloP100		0.63
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.15
Sift	Benign	0.081	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.62
MVP		0.55
MPC		0.30
ClinPred		0.0046	T
GERP RS		0.16
Varity_R		0.056
gMVP		0.35
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs78977446; hg19: chr9-136310917; COSMIC: COSV63020528;