NM_014244.5:c.1993G>A

Variant names:

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.1993G>A(p.Gly665Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,613,422 control chromosomes in the GnomAD database, including 187 homozygotes. 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G665G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0088 ( 11 hom., cov: 32)

Exomes 𝑓: 0.014 ( 176 hom. )

Consequence

ADAMTS2
NM_014244.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.13

Publications

15 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), G2P, Orphanet, Illumina, Genomics England PanelApp

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=0.0048826337).

BP6

Variant 5-179136001-C-T is Benign according to our data. Variant chr5-179136001-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 384810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00877 (1335/152254) while in subpopulation NFE AF = 0.015 (1022/68018). AF 95% confidence interval is 0.0143. There are 11 homozygotes in GnomAd4. There are 600 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014244.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	NM_014244.5	MANE Select	c.1993G>A	p.Gly665Arg	missense	Exon 13 of 22	NP_055059.2	O95450-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.1993G>A	p.Gly665Arg	missense	Exon 13 of 22	ENSP00000251582.7	O95450-1
ADAMTS2	ENST00000957641.1		c.1993G>A	p.Gly665Arg	missense	Exon 13 of 22	ENSP00000627700.1
ADAMTS2	ENST00000518335.3	TSL:3	c.1993G>A	p.Gly665Arg	missense	Exon 13 of 21	ENSP00000489888.2	A0A1B0GTY3

Frequencies

GnomAD3 genomes

AF:

0.00878

AC:

1335

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00265

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.00458

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00782

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0150

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00779

AC:

1958

AN:

251246

AF XY:

0.00753

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.00396

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00120

Gnomad FIN exome

AF:

0.00906

Gnomad NFE exome

AF:

0.0125

Gnomad OTH exome

AF:

0.00799

GnomAD4 exome

AF:

0.0135

AC:

19739

AN:

1461168

Hom.:

176

Cov.:

AF XY:

0.0132

AC XY:

9598

AN XY:

726886

show subpopulations

African (AFR)

AF:

0.00209

AC:

AN:

33480

American (AMR)

AF:

0.00398

AC:

178

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000803

AC:

AN:

26136

East Asian (EAS)

AF:

0.00106

AC:

AN:

39700

South Asian (SAS)

AF:

0.00294

AC:

254

AN:

86258

European-Finnish (FIN)

AF:

0.00857

AC:

452

AN:

52722

Middle Eastern (MID)

AF:

0.00225

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0162

AC:

18029

AN:

1111998

Other (OTH)

AF:

0.0113

AC:

680

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

1216

2431

3647

4862

6078

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

696

1392

2088

2784

3480

<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:

0.00877

AC:

1335

AN:

152254

Hom.:

Cov.:

AF XY:

0.00806

AC XY:

600

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00265

AC:

110

AN:

41556

American (AMR)

AF:

0.00458

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00136

AC:

AN:

5166

South Asian (SAS)

AF:

0.00249

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00782

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0150

AC:

1022

AN:

68018

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

128

193

257

321

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:

0.0108

Hom.:

Bravo

AF:

0.00776

TwinsUK

AF:

0.0148

AC:

ALSPAC

AF:

0.0171

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0142

AC:

122

ExAC

AF:

0.00785

AC:

953

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0123

EpiControl

AF:

0.0130

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Ehlers-Danlos syndrome, dermatosparaxis type (3)

Ehlers-Danlos syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.097

FATHMM_MKL

Benign

0.56

MetaRNN

Benign

0.0049

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.2

PhyloP100

2.1

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.5

REVEL

Benign

0.12

Sift

Benign

0.059

Sift4G

Benign

0.14

Polyphen

0.24

Vest4

0.33

MutPred

0.25

Gain of MoRF binding (P = 0.0138)

MVP

0.37

MPC

0.50

ClinPred

0.060

GERP RS

4.5

Varity_R

0.24

gMVP

0.71

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over