rs79330641

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014244.5(ADAMTS2):c.3014C>T(p.Ala1005Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,552,394 control chromosomes in the GnomAD database, including 23 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1005T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0067 ( 13 hom., cov: 33)

Exomes 𝑓: 0.00080 ( 10 hom. )

Consequence

ADAMTS2
NM_014244.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.149

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

Ehlers-Danlos syndrome, dermatosparaxis type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P, PanelApp Australia, Illumina

ADAMTS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041039586).

BP6

Variant 5-179122718-G-A is Benign according to our data. Variant chr5-179122718-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 390199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00671 (1022/152342) while in subpopulation AFR AF = 0.0228 (947/41572). AF 95% confidence interval is 0.0216. There are 13 homozygotes in GnomAd4. There are 482 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5 link	c.3014C>T	p.Ala1005Val	missense_variant	Exon 20 of 22	ENST00000251582.12	NP_055059.2	O95450-1
ADAMTS2	XM_047417895.1 link	c.2519C>T	p.Ala840Val	missense_variant	Exon 19 of 21		XP_047273851.1
ADAMTS2	XM_047417896.1 link	c.2132C>T	p.Ala711Val	missense_variant	Exon 18 of 20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12 link	c.3014C>T	p.Ala1005Val	missense_variant	Exon 20 of 22	1	NM_014244.5	ENSP00000251582.7		O95450-1

Frequencies

GnomAD3 genomes

AF:

0.00671

AC:

1022

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0228

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00307

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00765

GnomAD2 exomes

AF:

0.00161

AC:

253

AN:

157232

AF XY:

0.00126

show subpopulations

Gnomad AFR exome

AF:

0.0237

Gnomad AMR exome

AF:

0.00109

Gnomad ASJ exome

AF:

0.000235

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000148

Gnomad OTH exome

AF:

0.000901

GnomAD4 exome

AF:

0.000805

AC:

1127

AN:

1400052

Hom.:

Cov.:

AF XY:

0.000705

AC XY:

487

AN XY:

690698

show subpopulations

African (AFR)

AF:

0.0249

AC:

788

AN:

31702

American (AMR)

AF:

0.00159

AC:

AN:

35862

Ashkenazi Jewish (ASJ)

AF:

0.000159

AC:

AN:

25170

East Asian (EAS)

AF:

0.00

AC:

AN:

35850

South Asian (SAS)

AF:

0.000113

AC:

AN:

79336

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48320

Middle Eastern (MID)

AF:

0.00264

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.000112

AC:

121

AN:

1080036

Other (OTH)

AF:

0.00229

AC:

133

AN:

58086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

135

202

270

337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00671

AC:

1022

AN:

152342

Hom.:

Cov.:

AF XY:

0.00647

AC XY:

482

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0228

AC:

947

AN:

41572

American (AMR)

AF:

0.00300

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68036

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

100

149

199

249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00119

Hom.:

Bravo

AF:

0.00755

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0191

AC:

ESP6500EA

AF:

0.000474

AC:

ExAC

AF:

0.00101

AC:

108

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type

Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 02, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome

Benign:1

Dec 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Aug 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.057

MetaRNN

Benign

0.0041

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.17

N;.

PhyloP100

-0.15

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.8

N;.

REVEL

Benign

0.14

Sift

Benign

0.14

T;.

Sift4G

Benign

0.28

T;.

Polyphen

0.0070

B;.

Vest4

0.15

MVP

0.20

MPC

0.40

ClinPred

0.0053

GERP RS

-1.5

Varity_R

0.033

gMVP

0.18

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over