NM_139027.6:c.2699C>T

Variant names:

• chr9-133445787-C-T
• rs685523
• NM_139027.6:c.2699C>T

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.2699C>T​(p.Ala900Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.097 in 1,596,052 control chromosomes in the GnomAD database, including 8,223 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A900A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.10 (873 hom., cov: 32)
  • Exomes 𝑓: 0.096 (7350 hom.)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.69
• Publications: 35 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=0.0023660362).
• BP6: Variant 9-133445787-C-T is Benign according to our data. Variant chr9-133445787-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6	c.2699C>T	p.Ala900Val	missense_variant	Exon 21 of 29	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.2699C>T	p.Ala900Val	missense_variant	Exon 21 of 29	1	NM_139027.6	ENSP00000347927.2

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15796 AN: 152040 Hom.: 870 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.0736

Gnomad ASJ AF: 0.0516

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0259

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.101

GnomAD2 exomes AF: 0.0806 AC: 19610 AN: 243220 AF XY: 0.0789

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.0498

Gnomad ASJ exome AF: 0.0503

Gnomad EAS exome AF: 0.000328

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.0907

GnomAD4 exome AF: 0.0962 AC: 138955 AN: 1443894 Hom.: 7350 Cov.: 32 AF XY: 0.0940 AC XY: 67203 AN XY: 714746

African (AFR) AF: 0.143 AC: 4737 AN: 33180

American (AMR) AF: 0.0518 AC: 2289 AN: 44170

Ashkenazi Jewish (ASJ) AF: 0.0503 AC: 1289 AN: 25614

East Asian (EAS) AF: 0.000280 AC: 11 AN: 39250

South Asian (SAS) AF: 0.0312 AC: 2662 AN: 85388

European-Finnish (FIN) AF: 0.114 AC: 5981 AN: 52276

Middle Eastern (MID) AF: 0.0763 AC: 435 AN: 5702

European-Non Finnish (NFE) AF: 0.106 AC: 116142 AN: 1098826

Other (OTH) AF: 0.0909 AC: 5409 AN: 59488

GnomAD4 genome AF: 0.104 AC: 15820 AN: 152158 Hom.: 873 Cov.: 32 AF XY: 0.103 AC XY: 7637 AN XY: 74402

African (AFR) AF: 0.144 AC: 5960 AN: 41510

American (AMR) AF: 0.0737 AC: 1126 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0516 AC: 179 AN: 3470

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5172

South Asian (SAS) AF: 0.0263 AC: 127 AN: 4824

European-Finnish (FIN) AF: 0.105 AC: 1118 AN: 10610

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7048 AN: 67970

Other (OTH) AF: 0.0991 AC: 209 AN: 2110

Alfa AF: 0.101 Hom.: 1072

Bravo AF: 0.104

TwinsUK AF: 0.0982 AC: 364

ALSPAC AF: 0.112 AC: 431

ESP6500AA AF: 0.132 AC: 582

ESP6500EA AF: 0.103 AC: 887

ExAC AF: 0.0839 AC: 10179

Asia WGS AF: 0.0240 AC: 84 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19427680, 22768050) -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Upshaw-Schulman syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	7.5
DANN	Benign	0.16
DEOGEN2	Benign	0.033	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.00025	N
LIST_S2	Benign	0.22	T;T;T
MetaRNN	Benign	0.0024	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-2.3	N;N;.
PhyloP100		1.7
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.88	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.44	T;T;T
Sift4G	Benign	1.0	T;T;.
Polyphen		0.0	B;B;B
Vest4		0.019
MPC		0.33
ClinPred		0.00082	T
GERP RS		4.5
Varity_R		0.025
gMVP		0.26
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs685523; hg19: chr9-136310908; COSMIC: COSV63020147;