5-179345228-GGCGGCGGCGGCGGCGGCAGGA-GGCGGCGGCGGCGGCGGCAGGAGCGGCGGCGGCGGCGGCAGGA

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_014244.5(ADAMTS2):c.80_100dupTCCTGCCGCCGCCGCCGCCGC(p.Leu27_Pro33dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00538 in 147,388 control chromosomes in the GnomAD database, including 3 homozygotes. 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P34P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0054 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 7 hom. )

Failed GnomAD Quality Control

Consequence

ADAMTS2
NM_014244.5 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.24

Publications

0 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 -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_014244.5

BP6

Variant 5-179345228-G-GGCGGCGGCGGCGGCGGCAGGA is Benign according to our data. Variant chr5-179345228-G-GGCGGCGGCGGCGGCGGCAGGA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 420673.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 = 0.00538 (793/147388) while in subpopulation NFE AF = 0.00744 (495/66540). AF 95% confidence interval is 0.0069. There are 3 homozygotes in GnomAd4. There are 364 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	NM_014244.5	MANE Select	c.80_100dupTCCTGCCGCCGCCGCCGCCGC	p.Leu27_Pro33dup	conservative_inframe_insertion	Exon 1 of 22	NP_055059.2
	ADAMTS2	NM_021599.4		c.80_100dupTCCTGCCGCCGCCGCCGCCGC	p.Leu27_Pro33dup	conservative_inframe_insertion	Exon 1 of 11	NP_067610.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.80_100dupTCCTGCCGCCGCCGCCGCCGC	p.Leu27_Pro33dup	conservative_inframe_insertion	Exon 1 of 22	ENSP00000251582.7
ADAMTS2	ENST00000274609.5	TSL:1	c.80_100dupTCCTGCCGCCGCCGCCGCCGC	p.Leu27_Pro33dup	conservative_inframe_insertion	Exon 1 of 11	ENSP00000274609.5
ADAMTS2	ENST00000518335.3	TSL:3	c.80_100dupTCCTGCCGCCGCCGCCGCCGC	p.Leu27_Pro33dup	conservative_inframe_insertion	Exon 1 of 21	ENSP00000489888.2

Frequencies

GnomAD3 genomes

AF:

0.00538

AC:

793

AN:

147288

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00167

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00658

Gnomad ASJ

AF:

0.0205

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00106

Gnomad FIN

AF:

0.00442

Gnomad MID

AF:

0.00649

Gnomad NFE

AF:

0.00744

Gnomad OTH

AF:

0.00740

GnomAD2 exomes

AF:

0.00683

AC:

AN:

732

AF XY:

0.00242

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00760

Gnomad OTH exome

AF:

0.0714

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00250

AC:

2318

AN:

928860

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

1090

AN XY:

442302

show subpopulations

African (AFR)

AF:

0.000607

AC:

AN:

18116

American (AMR)

AF:

0.00132

AC:

AN:

4542

Ashkenazi Jewish (ASJ)

AF:

0.00474

AC:

AN:

8434

East Asian (EAS)

AF:

0.0000787

AC:

AN:

12708

South Asian (SAS)

AF:

0.000834

AC:

AN:

17988

European-Finnish (FIN)

AF:

0.000484

AC:

AN:

12396

Middle Eastern (MID)

AF:

0.00313

AC:

AN:

2236

European-Non Finnish (NFE)

AF:

0.00263

AC:

2152

AN:

818582

Other (OTH)

AF:

0.00236

AC:

AN:

33858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

184

275

367

459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

224

336

448

560

<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:

0.00538

AC:

793

AN:

147388

Hom.:

Cov.:

AF XY:

0.00507

AC XY:

364

AN XY:

71848

show subpopulations

African (AFR)

AF:

0.00166

AC:

AN:

40294

American (AMR)

AF:

0.00657

AC:

AN:

14920

Ashkenazi Jewish (ASJ)

AF:

0.0205

AC:

AN:

3418

East Asian (EAS)

AF:

0.00

AC:

AN:

4984

South Asian (SAS)

AF:

0.00106

AC:

AN:

4712

European-Finnish (FIN)

AF:

0.00442

AC:

AN:

9272

Middle Eastern (MID)

AF:

0.00694

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00744

AC:

495

AN:

66540

Other (OTH)

AF:

0.00732

AC:

AN:

2048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

109

146

182

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:

0.00215

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ehlers-Danlos syndrome, dermatosparaxis type (2)

not provided (2)

Ehlers-Danlos syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.2

Mutation Taster

=85/15

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over