rs371099308

Positions:

chr5-179137817-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014244.5(ADAMTS2):c.1903G>A(p.Glu635Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000242 in 1,580,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

ADAMTS2
NM_014244.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 0.806

Variant links:

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]

ADAMTS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1247949).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ADAMTS2	NM_014244.5 linkuse as main transcript	c.1903G>A	p.Glu635Lys	missense_variant	12/22	ENST00000251582.12	NP_055059.2
ADAMTS2	XM_047417895.1 linkuse as main transcript	c.1408G>A	p.Glu470Lys	missense_variant	11/21		XP_047273851.1
ADAMTS2	XM_047417896.1 linkuse as main transcript	c.1021G>A	p.Glu341Lys	missense_variant	10/20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12 linkuse as main transcript	c.1903G>A	p.Glu635Lys	missense_variant	12/22	1	NM_014244.5	ENSP00000251582	P2	O95450-1
ADAMTS2	ENST00000518335.3 linkuse as main transcript	c.1903G>A	p.Glu635Lys	missense_variant	12/21	3		ENSP00000489888	A2
ADAMTS2	ENST00000698889.1 linkuse as main transcript	c.1903G>A	p.Glu635Lys	missense_variant, NMD_transcript_variant	12/21			ENSP00000514008

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000155

AC:

AN:

194070

Hom.:

AF XY:

0.000219

AC XY:

AN XY:

104864

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000345

Gnomad SAS exome

AF:

0.000161

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000254

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000254

AC:

363

AN:

1427968

Hom.:

Cov.:

AF XY:

0.000263

AC XY:

186

AN XY:

707540

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000489

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000107

Gnomad4 SAS exome

AF:

0.000308

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000288

Gnomad4 OTH exome

AF:

0.000254

GnomAD4 genome

AF:

0.000125

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000133

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.000151

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 635 of the ADAMTS2 protein (p.Glu635Lys). This variant is present in population databases (rs371099308, gnomAD 0.02%). 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: 469667). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15". The lysine 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, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2019	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2023	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 17, 2019	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.1903G>A (p.E635K) alteration is located in exon 12 (coding exon 12) of the ADAMTS2 gene. This alteration results from a G to A substitution at nucleotide position 1903, causing the glutamic acid (E) at amino acid position 635 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.089

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.

Eigen

Benign

0.039

Eigen_PC

Benign

0.0032

FATHMM_MKL

Uncertain

0.80

M_CAP

Benign

0.026

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

2.0

M;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-2.2

N;.

REVEL

Uncertain

0.39

Sift

Benign

0.064

T;.

Sift4G

Benign

0.44

T;.

Polyphen

0.99

D;.

Vest4

0.34

MutPred

0.62

Loss of stability (P = 0.0048);Loss of stability (P = 0.0048);

MVP

0.88

MPC

0.85

ClinPred

0.10

GERP RS

3.8

Varity_R

0.20

gMVP

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over