9-133422462-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_139027.6(ADAMTS13):c.19C>T(p.Arg7Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,613,772 control chromosomes in the GnomAD database, including 11,180 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R7Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.093 (802 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10378 hom.)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.39

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015433729).
• BP6: Variant 9-133422462-C-T is Benign according to our data. Variant chr9-133422462-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 262432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133422462-C-T is described in Lovd as [Benign]. Variant chr9-133422462-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS13	NM_139027.6	c.19C>T	p.Arg7Trp	missense_variant	1/29	ENST00000355699.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.19C>T	p.Arg7Trp	missense_variant	1/29	1	NM_139027.6	A2

Frequencies

GnomAD3 genomes AF: 0.0928 AC: 14117 AN: 152150 Hom.: 802 Cov.: 32

Gnomad AFR AF: 0.0482

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.0759

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0383

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.0910

GnomAD3 exomes AF: 0.0906 AC: 22741 AN: 251060 Hom.: 1352 AF XY: 0.0918 AC XY: 12463 AN XY: 135728

Gnomad AFR exome AF: 0.0454

Gnomad AMR exome AF: 0.0513

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.00217

Gnomad SAS exome AF: 0.0426

Gnomad FIN exome AF: 0.122

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.0996

GnomAD4 exome AF: 0.113 AC: 165459 AN: 1461504 Hom.: 10378 Cov.: 32 AF XY: 0.111 AC XY: 80750 AN XY: 727092

Gnomad4 AFR exome AF: 0.0454

Gnomad4 AMR exome AF: 0.0530

Gnomad4 ASJ exome AF: 0.0994

Gnomad4 EAS exome AF: 0.00237

Gnomad4 SAS exome AF: 0.0429

Gnomad4 FIN exome AF: 0.121

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.0928 AC: 14123 AN: 152268 Hom.: 802 Cov.: 32 AF XY: 0.0924 AC XY: 6881 AN XY: 74462

Gnomad4 AFR AF: 0.0483

Gnomad4 AMR AF: 0.0759

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.00290

Gnomad4 SAS AF: 0.0384

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.128

Gnomad4 OTH AF: 0.0896

Alfa AF: 0.112 Hom.: 2003

Bravo AF: 0.0882

TwinsUK AF: 0.133 AC: 492

ALSPAC AF: 0.139 AC: 534

ESP6500AA AF: 0.0517 AC: 228

ESP6500EA AF: 0.125 AC: 1071

ExAC AF: 0.0938 AC: 11390

Asia WGS AF: 0.0260 AC: 90 AN: 3478

EpiCase AF: 0.125

EpiControl AF: 0.125

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	Nov 10, 2018	This variant is associated with the following publications: (PMID: 12614216, 16160007, 32531546) -

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	0.083
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	0.38
Dann	Benign	0.68
DEOGEN2	Benign	0.064	T;.;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.66	T;T;T;T
MetaRNN	Benign	0.0015	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.75	N;.;N;N
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.48	N;N;N;N
REVEL	Benign	0.056
Sift	Benign	0.090	T;T;T;T
Sift4G	Benign	0.10	T;T;T;.
Polyphen		0.0	B;.;B;B
Vest4		0.054
MPC		0.35
ClinPred		0.00086	T
GERP RS		-6.5
Varity_R		0.054
gMVP		0.39

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: rs34024143; hg19: chr9-136287582; COSMIC: COSV63020622; COSMIC: COSV63020622;