rs147438064

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_014244.5(ADAMTS2):c.1488C>T(p.Phe496Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,610,534 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0028 ( 9 hom. )

Consequence

ADAMTS2
NM_014244.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.545

Publications

1 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 5-179153518-G-A is Benign according to our data. Variant chr5-179153518-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 381211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.545 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00283 (4127/1458276) while in subpopulation NFE AF = 0.00339 (3766/1111870). AF 95% confidence interval is 0.0033. There are 9 homozygotes in GnomAdExome4. There are 2048 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5 link	c.1488C>T	p.Phe496Phe	synonymous_variant	Exon 9 of 22	ENST00000251582.12	NP_055059.2	O95450-1
ADAMTS2	NM_021599.4 link	c.1488C>T	p.Phe496Phe	synonymous_variant	Exon 9 of 11		NP_067610.1	O95450-2
ADAMTS2	XM_047417895.1 link	c.993C>T	p.Phe331Phe	synonymous_variant	Exon 8 of 21		XP_047273851.1
ADAMTS2	XM_047417896.1 link	c.606C>T	p.Phe202Phe	synonymous_variant	Exon 7 of 20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADAMTS2	ENST00000251582.12 link	c.1488C>T	p.Phe496Phe	synonymous_variant	Exon 9 of 22	1	NM_014244.5	ENSP00000251582.7	O95450-1
ADAMTS2	ENST00000274609.5 link	c.1488C>T	p.Phe496Phe	synonymous_variant	Exon 9 of 11	1		ENSP00000274609.5	O95450-2
ADAMTS2	ENST00000518335.3 link	c.1488C>T	p.Phe496Phe	synonymous_variant	Exon 9 of 21	3		ENSP00000489888.2	A0A1B0GTY3
ADAMTS2	ENST00000698889.1 link	n.1488C>T		non_coding_transcript_exon_variant	Exon 9 of 21			ENSP00000514008.1	A0A8V8TMU7

Frequencies

GnomAD3 genomes

AF:

0.00177

AC:

269

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00367

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00300

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00208

AC:

513

AN:

247222

AF XY:

0.00192

show subpopulations

Gnomad AFR exome

AF:

0.000560

Gnomad AMR exome

AF:

0.000464

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00410

Gnomad NFE exome

AF:

0.00351

Gnomad OTH exome

AF:

0.00247

GnomAD4 exome

AF:

0.00283

AC:

4127

AN:

1458276

Hom.:

Cov.:

AF XY:

0.00282

AC XY:

2048

AN XY:

725670

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33476

American (AMR)

AF:

0.000425

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00450

AC:

225

AN:

50042

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00339

AC:

3766

AN:

1111870

Other (OTH)

AF:

0.00162

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

268

536

805

1073

1341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

264

396

528

660

<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:

0.00177

AC:

269

AN:

152258

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

115

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41554

American (AMR)

AF:

0.000523

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00367

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00300

AC:

204

AN:

68006

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00211

Hom.:

Bravo

AF:

0.00155

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00207

EpiControl

AF:

0.00267

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ADAMTS2: BP4, BP7 -

Apr 19, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome, dermatosparaxis type

Benign:3

Oct 21, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified

Benign:1

Aug 15, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome

Benign:1

Mar 19, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

7.8

(source)

DANN

Benign

0.74

PhyloP100

-0.55

Mutation Taster

=91/9

polymorphism

(source)

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

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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