rs281875307

chr9-133442447-A-Gchr9-133442447-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_139027.6(ADAMTS13):c.2017A>G(p.Ile673Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I673F) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.686

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a region_of_interest Spacer (size 129) in uniprot entity ATS13_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_139027.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-133442447-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68809.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08926132).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS13	NM_139027.6	c.2017A>G	p.Ile673Val	missense_variant	17/29	ENST00000355699.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.2017A>G	p.Ile673Val	missense_variant	17/29	1	NM_139027.6	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251280 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461562 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727088

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	5.8
Dann	Benign	0.58
DEOGEN2	Benign	0.095	T;.;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.62	T;T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.089	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L;L;.
MutationTaster	Benign	0.65	D;D;D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.37	N;N;N
REVEL	Benign	0.053
Sift	Benign	0.56	T;T;T
Sift4G	Benign	0.062	T;T;.
Polyphen		0.011	B;B;B
Vest4		0.26
MutPred		0.49		Gain of phosphorylation at Y677 (P = 0.0916);Gain of phosphorylation at Y677 (P = 0.0916);.;
MVP		0.65
MPC		0.29
ClinPred		0.010	T
GERP RS		1.6
Varity_R		0.057
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs281875307; hg19: chr9-136307568;