rs28647808

chr9-133440409-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_139027.6(ADAMTS13):c.1852C>G(p.Pro618Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0759 in 1,613,908 control chromosomes in the GnomAD database, including 5,313 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (353 hom., cov: 32)
  • Exomes 𝑓: 0.078 (4960 hom.)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.56

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a region_of_interest Spacer (size 129) in uniprot entity ATS13_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_139027.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.0041890144).
• BP6: Variant 9-133440409-C-G is Benign according to our data. Variant chr9-133440409-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 262430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133440409-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0877 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS13	NM_139027.6	c.1852C>G	p.Pro618Ala	missense_variant	16/29	ENST00000355699.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.1852C>G	p.Pro618Ala	missense_variant	16/29	1	NM_139027.6	A2

Frequencies

GnomAD3 genomes AF: 0.0580 AC: 8825 AN: 152176 Hom.: 354 Cov.: 32

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.0487

Gnomad ASJ AF: 0.0760

Gnomad EAS AF: 0.0199

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0617

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0896

Gnomad OTH AF: 0.0630

GnomAD3 exomes AF: 0.0605 AC: 15192 AN: 251016 Hom.: 641 AF XY: 0.0609 AC XY: 8274 AN XY: 135834

Gnomad AFR exome AF: 0.0153

Gnomad AMR exome AF: 0.0327

Gnomad ASJ exome AF: 0.0741

Gnomad EAS exome AF: 0.0187

Gnomad SAS exome AF: 0.0227

Gnomad FIN exome AF: 0.0624

Gnomad NFE exome AF: 0.0904

Gnomad OTH exome AF: 0.0693

GnomAD4 exome AF: 0.0778 AC: 113718 AN: 1461614 Hom.: 4960 Cov.: 36 AF XY: 0.0760 AC XY: 55271 AN XY: 727110

Gnomad4 AFR exome AF: 0.0128

Gnomad4 AMR exome AF: 0.0341

Gnomad4 ASJ exome AF: 0.0731

Gnomad4 EAS exome AF: 0.0232

Gnomad4 SAS exome AF: 0.0225

Gnomad4 FIN exome AF: 0.0622

Gnomad4 NFE exome AF: 0.0891

Gnomad4 OTH exome AF: 0.0710

GnomAD4 genome AF: 0.0579 AC: 8822 AN: 152294 Hom.: 353 Cov.: 32 AF XY: 0.0571 AC XY: 4254 AN XY: 74476

Gnomad4 AFR AF: 0.0162

Gnomad4 AMR AF: 0.0487

Gnomad4 ASJ AF: 0.0760

Gnomad4 EAS AF: 0.0199

Gnomad4 SAS AF: 0.0232

Gnomad4 FIN AF: 0.0617

Gnomad4 NFE AF: 0.0896

Gnomad4 OTH AF: 0.0619

Alfa AF: 0.0805 Hom.: 432

Bravo AF: 0.0556

TwinsUK AF: 0.0928 AC: 344

ALSPAC AF: 0.0955 AC: 368

ESP6500AA AF: 0.0179 AC: 79

ESP6500EA AF: 0.0863 AC: 742

ExAC AF: 0.0629 AC: 7635

Asia WGS AF: 0.0380 AC: 130 AN: 3478

EpiCase AF: 0.0863

EpiControl AF: 0.0878

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 16160007, 26139087, 26284228, 28939980, 23733198, 32531546, 23847193, 22768050, 25934476, 12614216) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Upshaw-Schulman syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D;D
MetaRNN	Benign	0.0042	T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Pathogenic	2.9	M;.;M;.
MutationTaster	Benign	0.000027	P;P;P;P;P
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.5	D;.;D;D
REVEL	Uncertain	0.30
Sift	Benign	0.050	D;.;D;T
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;.;D;D
Vest4		0.59
MPC		0.64
ClinPred		0.010	T
GERP RS		5.1
Varity_R		0.27
gMVP		0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs28647808; hg19: chr9-136305530; COSMIC: COSV63020057;