9-133436862-C-G

Variant names:

• chr9-133436862-C-G
• rs2301612
• NM_139027.6:c.1342C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 16/21 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
• Publications: 67 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=0.0034115016).
• BP6: Variant 9-133436862-C-G is Benign according to our data. Variant chr9-133436862-C-G is described in ClinVar as Benign. ClinVar VariationId is 242806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6	c.1342C>G	p.Gln448Glu	missense_variant	Exon 12 of 29	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.1342C>G	p.Gln448Glu	missense_variant	Exon 12 of 29	1	NM_139027.6	ENSP00000347927.2

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

GnomAD2 exomes AF: 0.379 AC: 78625 AN: 207396 AF XY: 0.384

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 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

African (AFR) AF: 0.0781 AC: 2578 AN: 33016

American (AMR) AF: 0.395 AC: 16149 AN: 40910

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 7524 AN: 25464

East Asian (EAS) AF: 0.193 AC: 7375 AN: 38282

South Asian (SAS) AF: 0.431 AC: 35595 AN: 82538

European-Finnish (FIN) AF: 0.486 AC: 24207 AN: 49844

Middle Eastern (MID) AF: 0.286 AC: 1630 AN: 5692

European-Non Finnish (NFE) AF: 0.436 AC: 478216 AN: 1097708

Other (OTH) AF: 0.379 AC: 22408 AN: 59140

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

African (AFR) AF: 0.0884 AC: 3636 AN: 41118

American (AMR) AF: 0.349 AC: 5273 AN: 15104

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1014 AN: 3460

East Asian (EAS) AF: 0.189 AC: 955 AN: 5042

South Asian (SAS) AF: 0.429 AC: 2033 AN: 4742

European-Finnish (FIN) AF: 0.481 AC: 4973 AN: 10336

Middle Eastern (MID) AF: 0.257 AC: 75 AN: 292

European-Non Finnish (NFE) AF: 0.433 AC: 29280 AN: 67662

Other (OTH) AF: 0.299 AC: 626 AN: 2096

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

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Upshaw-Schulman syndrome Benign:2

Aug 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.
PhyloP100		3.3
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
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

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