rs36220239

Positions:

• chr9-133436888-G-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.1368G>T​(p.Gln456His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,586,750 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. Q456E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (60 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (70 hom.)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.21

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=0.0053318143).
• BP6: Variant 9-133436888-G-T is Benign according to our data. Variant chr9-133436888-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 262426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS13	NM_139027.6	c.1368G>T	p.Gln456His	missense_variant	12/29	ENST00000355699.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.1368G>T	p.Gln456His	missense_variant	12/29	1	NM_139027.6	A2

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2265 AN: 151396 Hom.: 60 Cov.: 31

Gnomad AFR AF: 0.0525

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00490

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00816

GnomAD3 exomes AF: 0.00362 AC: 736 AN: 203046 Hom.: 17 AF XY: 0.00260 AC XY: 286 AN XY: 109864

Gnomad AFR exome AF: 0.0520

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000102

Gnomad OTH exome AF: 0.00194

GnomAD4 exome AF: 0.00154 AC: 2207 AN: 1435238 Hom.: 70 Cov.: 35 AF XY: 0.00127 AC XY: 904 AN XY: 711346

Gnomad4 AFR exome AF: 0.0536

Gnomad4 AMR exome AF: 0.00310

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000607

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000700

Gnomad4 OTH exome AF: 0.00339

GnomAD4 genome AF: 0.0149 AC: 2264 AN: 151512 Hom.: 60 Cov.: 31 AF XY: 0.0148 AC XY: 1094 AN XY: 73986

Gnomad4 AFR AF: 0.0523

Gnomad4 AMR AF: 0.00489

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00807

Alfa AF: 0.00258 Hom.: 9

Bravo AF: 0.0169

ESP6500AA AF: 0.0495 AC: 216

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00414 AC: 494

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

Upshaw-Schulman syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.36	T;T;.;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.58	T;T;T;T
MetaRNN	Benign	0.0053	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.;L;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.6	D;.;D;D
REVEL	Benign	0.088
Sift	Benign	0.072	T;.;D;D
Sift4G	Benign	0.092	T;T;T;.
Polyphen		0.0020	B;.;B;B
Vest4		0.13
MutPred		0.17		Gain of catalytic residue at L458 (P = 0.0878);.;Gain of catalytic residue at L458 (P = 0.0878);.;
MVP		0.74
MPC		0.32
ClinPred		0.023	T
GERP RS		-1.4
Varity_R		0.047
gMVP		0.68

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: rs36220239; hg19: chr9-136302008;