9-133436862-C-G

Position:

• chr9-133436862-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.1342C>G​(p.Gln448Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 1,583,348 control chromosomes in the GnomAD database, including 137,791 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (9566 hom., cov: 28)
  • Exomes 𝑓: 0.42 (128225 hom.)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.29

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 Cysteine-rich (size 116) in uniprot entity ATS13_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_139027.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.0034115016).
• BP6: Variant 9-133436862-C-G is Benign according to our data. Variant chr9-133436862-C-G is described in ClinVar as [Benign]. Clinvar id is 242806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133436862-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.429 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS13	NM_139027.6	c.1342C>G	p.Gln448Glu	missense_variant	12/29	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.1342C>G	p.Gln448Glu	missense_variant	12/29	1	NM_139027.6	ENSP00000347927	A2

Frequencies

GnomAD3 genomes AF: 0.319 AC: 48121 AN: 150640 Hom.: 9560 Cov.: 28

Gnomad AFR AF: 0.0885

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.301

GnomAD3 exomes AF: 0.379 AC: 78625 AN: 207396 Hom.: 16115 AF XY: 0.384 AC XY: 43074 AN XY: 112054

Gnomad AFR exome AF: 0.0802

Gnomad AMR exome AF: 0.398

Gnomad ASJ exome AF: 0.289

Gnomad EAS exome AF: 0.181

Gnomad SAS exome AF: 0.432

Gnomad FIN exome AF: 0.475

Gnomad NFE exome AF: 0.425

Gnomad OTH exome AF: 0.379

GnomAD4 exome AF: 0.416 AC: 595682 AN: 1432594 Hom.: 128225 Cov.: 47 AF XY: 0.417 AC XY: 296086 AN XY: 709982

Gnomad4 AFR exome AF: 0.0781

Gnomad4 AMR exome AF: 0.395

Gnomad4 ASJ exome AF: 0.295

Gnomad4 EAS exome AF: 0.193

Gnomad4 SAS exome AF: 0.431

Gnomad4 FIN exome AF: 0.486

Gnomad4 NFE exome AF: 0.436

Gnomad4 OTH exome AF: 0.379

GnomAD4 genome AF: 0.319 AC: 48134 AN: 150754 Hom.: 9566 Cov.: 28 AF XY: 0.323 AC XY: 23764 AN XY: 73560

Gnomad4 AFR AF: 0.0884

Gnomad4 AMR AF: 0.349

Gnomad4 ASJ AF: 0.293

Gnomad4 EAS AF: 0.189

Gnomad4 SAS AF: 0.429

Gnomad4 FIN AF: 0.481

Gnomad4 NFE AF: 0.433

Gnomad4 OTH AF: 0.299

Alfa AF: 0.399 Hom.: 4372

Bravo AF: 0.293

TwinsUK AF: 0.440 AC: 1633

ALSPAC AF: 0.423 AC: 1631

ESP6500AA AF: 0.0959 AC: 421

ESP6500EA AF: 0.406 AC: 3485

ExAC AF: 0.344 AC: 40802

Asia WGS AF: 0.305 AC: 1061 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Upshaw-Schulman syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 16, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.21
DEOGEN2	Benign	0.062	T;T;.;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.41	T;T;T;T
MetaRNN	Benign	0.0034	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.3	N;.;N;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	1.8	N;.;N;N
REVEL	Benign	0.076
Sift	Benign	1.0	T;.;T;T
Sift4G	Benign	1.0	T;T;T;.
Polyphen		0.0	B;.;B;B
Vest4		0.066
MPC		0.36
ClinPred		0.0021	T
GERP RS		4.3
Varity_R		0.27
gMVP		0.56

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: rs2301612; hg19: chr9-136301982; COSMIC: COSV63021033;