rs36090624

Positions:

• chr9-133440431-G-A
• chr9-133440431-G-T

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.1874G>A​(p.Arg625His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,613,770 control chromosomes in the GnomAD database, including 195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (113 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (82 hom.)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.92

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 (HGNC:):

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 5 pathogenic changes around while only 0 benign (100%) in NM_139027.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.00303033).
• BP6: Variant 9-133440431-G-A is Benign according to our data. Variant chr9-133440431-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 262431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133440431-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0681 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS13	NM_139027.6	c.1874G>A	p.Arg625His	missense_variant	16/29	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.1874G>A	p.Arg625His	missense_variant	16/29	1	NM_139027.6	ENSP00000347927.2

Frequencies

GnomAD3 genomes AF: 0.0201 AC: 3056 AN: 152102 Hom.: 113 Cov.: 32

Gnomad AFR AF: 0.0702

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00674

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: 0.000176

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.00534 AC: 1341 AN: 250902 Hom.: 32 AF XY: 0.00401 AC XY: 545 AN XY: 135826

Gnomad AFR exome AF: 0.0728

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00208 AC: 3035 AN: 1461550 Hom.: 82 Cov.: 35 AF XY: 0.00177 AC XY: 1285 AN XY: 727068

Gnomad4 AFR exome AF: 0.0713

Gnomad4 AMR exome AF: 0.00420

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000171

Gnomad4 OTH exome AF: 0.00407

GnomAD4 genome AF: 0.0201 AC: 3064 AN: 152220 Hom.: 113 Cov.: 32 AF XY: 0.0190 AC XY: 1414 AN XY: 74418

Gnomad4 AFR AF: 0.0702

Gnomad4 AMR AF: 0.00673

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00594 Hom.: 36

Bravo AF: 0.0230

ESP6500AA AF: 0.0776 AC: 342

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00698 AC: 847

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2020	This variant is associated with the following publications: (PMID: 25242241) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	0.090
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T;.;.
Eigen	Benign	0.045
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.78	T;T;T;T
MetaRNN	Benign	0.0030	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.4	M;.;M;.
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.5	D;.;D;N
REVEL	Uncertain	0.31
Sift	Benign	0.23	T;.;T;T
Sift4G	Uncertain	0.020	D;T;D;.
Polyphen		1.0	D;.;D;D
Vest4		0.28
MVP		0.87
MPC		0.58
ClinPred		0.030	T
GERP RS		4.1
Varity_R		0.097
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs36090624; hg19: chr9-136305552;