5-179345258-GGCAGCAGCAGCAGCA-GGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_014244.5(ADAMTS2):c.56_70dupTGCTGCTGCTGCTGC(p.Leu19_Leu23dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 147,072 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ADAMTS2
NM_014244.5 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.00

Publications

6 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5 link	c.56_70dupTGCTGCTGCTGCTGC	p.Leu19_Leu23dup	conservative_inframe_insertion	Exon 1 of 22	ENST00000251582.12	NP_055059.2	O95450-1
ADAMTS2	NM_021599.4 link	c.56_70dupTGCTGCTGCTGCTGC	p.Leu19_Leu23dup	conservative_inframe_insertion	Exon 1 of 11		NP_067610.1	O95450-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADAMTS2	ENST00000251582.12 link	c.56_70dupTGCTGCTGCTGCTGC	p.Leu19_Leu23dup	conservative_inframe_insertion	Exon 1 of 22	1	NM_014244.5	ENSP00000251582.7	O95450-1
ADAMTS2	ENST00000274609.5 link	c.56_70dupTGCTGCTGCTGCTGC	p.Leu19_Leu23dup	conservative_inframe_insertion	Exon 1 of 11	1		ENSP00000274609.5	O95450-2
ADAMTS2	ENST00000518335.3 link	c.56_70dupTGCTGCTGCTGCTGC	p.Leu19_Leu23dup	conservative_inframe_insertion	Exon 1 of 21	3		ENSP00000489888.2	A0A1B0GTY3
ADAMTS2	ENST00000698889.1 link	n.56_70dupTGCTGCTGCTGCTGC		non_coding_transcript_exon_variant	Exon 1 of 21			ENSP00000514008.1	A0A8V8TMU7

Frequencies

GnomAD3 genomes

AF:

0.0000204

AC:

AN:

146980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000250

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000134

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000212

AC:

AN:

989358

Hom.:

Cov.:

AF XY:

0.0000233

AC XY:

AN XY:

472146

show subpopulations

African (AFR)

AF:

0.000105

AC:

AN:

19040

American (AMR)

AF:

0.00

AC:

AN:

5490

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9740

East Asian (EAS)

AF:

0.000315

AC:

AN:

15854

South Asian (SAS)

AF:

0.00

AC:

AN:

18838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

15280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2440

European-Non Finnish (NFE)

AF:

0.0000162

AC:

AN:

865856

Other (OTH)

AF:

0.00

AC:

AN:

36820

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.430

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000204

AC:

AN:

147072

Hom.:

Cov.:

AF XY:

0.0000279

AC XY:

AN XY:

71648

show subpopulations

African (AFR)

AF:

0.0000250

AC:

AN:

40070

American (AMR)

AF:

0.000134

AC:

AN:

14928

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3404

East Asian (EAS)

AF:

0.00

AC:

AN:

4946

South Asian (SAS)

AF:

0.00

AC:

AN:

4780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66382

Other (OTH)

AF:

0.00

AC:

AN:

2064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type

Uncertain:1

Sep 17, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.56_70dup, results in the insertion of 5 amino acid(s) to the ADAMTS2 protein (p.Leu19_Leu23dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with ADAMTS2-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

not provided

Uncertain:1

Jan 25, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

Mutation Taster

=72/28

polymorphism

(source)

Splicing

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