rs138014548

Variant names:

• chr9-133442676-C-A
• rs138014548
• NM_139027.6:c.2167C>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS1

The NM_139027.6(ADAMTS13):​c.2167C>A​(p.Gln723Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,613,142 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -1.08

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

Our verdict: Benign. The variant received -7 ACMG points.

• PM1: In a domain TSP type-1 2 (size 48) in uniprot entity ATS13_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_139027.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.017062008).
• BP6: Variant 9-133442676-C-A is Benign according to our data. Variant chr9-133442676-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225292.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000167 (244/1460768) while in subpopulation EAS AF = 0.0061 (242/39696). AF 95% confidence interval is 0.00547. There are 1 homozygotes in GnomAdExome4. There are 127 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position FAILED quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6	c.2167C>A	p.Gln723Lys	missense_variant	Exon 18 of 29	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.2167C>A	p.Gln723Lys	missense_variant	Exon 18 of 29	1	NM_139027.6	ENSP00000347927.2

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152256 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000960 AC: 24 AN: 250064 AF XY: 0.0000959

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00126

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000167 AC: 244 AN: 1460768 Hom.: 1 Cov.: 32 AF XY: 0.000175 AC XY: 127 AN XY: 726706

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33480

Gnomad4 AMR exome AF: 0.0000224 AC: 1 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26132

Gnomad4 EAS exome AF: 0.00610 AC: 242 AN: 39696

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52350

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1111986

Gnomad4 Remaining exome AF: 0.0000166 AC: 1 AN: 60374

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152374 Hom.: 0 Cov.: 33 AF XY: 0.0000939 AC XY: 7 AN XY: 74514

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00154 AC: 0.00154143 AN: 0.00154143

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000173 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.000148 AC: 18

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Upshaw-Schulman syndrome Uncertain:1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

not provided Uncertain:1

Apr 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 225292). This missense change has been observed in individual(s) with Upshaw-Schulman syndrome (PMID: 21781265). This variant is present in population databases (rs138014548, gnomAD 0.1%). This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 723 of the ADAMTS13 protein (p.Gln723Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	0.19
DANN	Benign	0.51
DEOGEN2	Benign	0.042	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.45	T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.017	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;.
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.30	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.33	T;T;.
Polyphen		0.014	B;B;B
Vest4		0.064
MVP		0.58
MPC		0.43
ClinPred		0.018	T
GERP RS		-1.5
Varity_R		0.044
gMVP		0.49
Mutation Taster		=18/82	disease causing

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: rs138014548; hg19: chr9-136307797; COSMIC: COSV63022859;