chr5-179153548-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_014244.5(ADAMTS2):c.1458C>T(p.Tyr486Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00415 in 1,610,818 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0042 ( 23 hom. )

Consequence

ADAMTS2
NM_014244.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.79

Publications

3 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 5-179153548-G-A is Benign according to our data. Variant chr5-179153548-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 353121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.79 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0041 (624/152260) while in subpopulation NFE AF = 0.00553 (376/68002). AF 95% confidence interval is 0.00507. There are 4 homozygotes in GnomAd4. There are 331 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5 link	c.1458C>T	p.Tyr486Tyr	synonymous_variant	Exon 9 of 22	ENST00000251582.12	NP_055059.2	O95450-1
ADAMTS2	NM_021599.4 link	c.1458C>T	p.Tyr486Tyr	synonymous_variant	Exon 9 of 11		NP_067610.1	O95450-2
ADAMTS2	XM_047417895.1 link	c.963C>T	p.Tyr321Tyr	synonymous_variant	Exon 8 of 21		XP_047273851.1
ADAMTS2	XM_047417896.1 link	c.576C>T	p.Tyr192Tyr	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.1458C>T	p.Tyr486Tyr	synonymous_variant	Exon 9 of 22	1	NM_014244.5	ENSP00000251582.7	O95450-1
ADAMTS2	ENST00000274609.5 link	c.1458C>T	p.Tyr486Tyr	synonymous_variant	Exon 9 of 11	1		ENSP00000274609.5	O95450-2
ADAMTS2	ENST00000518335.3 link	c.1458C>T	p.Tyr486Tyr	synonymous_variant	Exon 9 of 21	3		ENSP00000489888.2	A0A1B0GTY3
ADAMTS2	ENST00000698889.1 link	n.1458C>T		non_coding_transcript_exon_variant	Exon 9 of 21			ENSP00000514008.1	A0A8V8TMU7

Frequencies

GnomAD3 genomes

AF:

0.00410

AC:

624

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0178

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00553

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00418

AC:

1032

AN:

246670

AF XY:

0.00409

show subpopulations

Gnomad AFR exome

AF:

0.000499

Gnomad AMR exome

AF:

0.00105

Gnomad ASJ exome

AF:

0.00280

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0183

Gnomad NFE exome

AF:

0.00502

Gnomad OTH exome

AF:

0.00314

GnomAD4 exome

AF:

0.00416

AC:

6066

AN:

1458558

Hom.:

Cov.:

AF XY:

0.00417

AC XY:

3029

AN XY:

725710

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33474

American (AMR)

AF:

0.00101

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00203

AC:

AN:

26118

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39688

South Asian (SAS)

AF:

0.000986

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.0166

AC:

839

AN:

50402

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00431

AC:

4797

AN:

1111844

Other (OTH)

AF:

0.00378

AC:

228

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

373

746

1120

1493

1866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

146

292

438

584

730

<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:

0.00410

AC:

624

AN:

152260

Hom.:

Cov.:

AF XY:

0.00445

AC XY:

331

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41548

American (AMR)

AF:

0.000980

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00166

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0178

AC:

189

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00553

AC:

376

AN:

68002

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

125

156

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:

0.00502

Hom.:

Bravo

AF:

0.00253

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00458

EpiControl

AF:

0.00380

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type

Benign:4

Oct 18, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

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. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jul 31, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ADAMTS2: BP4, BP7, BS2 -

not specified

Benign:1

Dec 26, 2018

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ADAMTS2 c.1458C>T alters a conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0046 in 272964 control chromosomes, including 7 homozygotes (gnomAD). The observed variant frequency within Finnish control individuals (0.018) in the gnomAD database is approximately 6-fold of the estimated maximal expected allele frequency for a pathogenic variant in ADAMTS2 causing Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) phenotype (0.0029), strongly suggesting that the variant is a benign polymorphism. To our knowledge, no occurrence of c.1458C>T in individuals affected with Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2 classifying it as benign/likely benign and 1 as VUS). Based on the evidence outlined above, the variant was classified as benign. -

Ehlers-Danlos syndrome

Benign:1

Apr 04, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: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

-0.51

CADD

Benign

5.4

(source)

DANN

Benign

0.66

PhyloP100

2.8

Mutation Taster

=100/0

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