rs200982805

Positions:

• chr5-179114054-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_014244.5(ADAMTS2):​c.3449A>G​(p.Asn1150Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,614,098 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: ADAMTS2 NM_014244.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 B:1
• Conservation: PhyloP100: 3.27

Genes affected

ADAMTS2 (HGNC:218): (ADAM metallopeptidase with thrombospondin type 1 motif 2) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of the family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The encoded preproprotein is proteolytically processed to generate the mature procollagen N-proteinase. This proteinase excises the N-propeptide of the fibrillar procollagens types I-III and type V. Mutations in this gene cause Ehlers-Danlos syndrome type VIIC, a recessively inherited connective-tissue disorder. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity ATS2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06711465).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS2	NM_014244.5	c.3449A>G	p.Asn1150Ser	missense_variant	22/22	ENST00000251582.12
ADAMTS2	XM_047417895.1	c.2954A>G	p.Asn985Ser	missense_variant	21/21
ADAMTS2	XM_047417896.1	c.2567A>G	p.Asn856Ser	missense_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.3449A>G	p.Asn1150Ser	missense_variant	22/22	1	NM_014244.5	P2
ADAMTS2	ENST00000522937.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000135 AC: 34 AN: 251496 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135922

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000168 AC: 246 AN: 1461894 Hom.: 1 Cov.: 32 AF XY: 0.000182 AC XY: 132 AN XY: 727248

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74414

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 21, 2022	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1150 of the ADAMTS2 protein (p.Asn1150Ser). This variant is present in population databases (rs200982805, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ADAMTS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 353086). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 01, 2020	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 19, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Uncertain	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.59	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.088
Sift	Benign	0.47	T
Sift4G	Benign	0.63	T
Polyphen		0.65	P
Vest4		0.12
MVP		0.60
MPC		0.33
ClinPred		0.037	T
GERP RS		3.9
Varity_R		0.049
gMVP		0.12

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: rs200982805; hg19: chr5-178541055;