5-179345228-GGCGGCGGCGGCGGCGGCAGGA-GGCGGCGGCGGCGGCGGCAGGAGCGGCGGCGGCGGCGGCAGGAGCGGCGGCGGCGGCGGCAGGA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_014244.5(ADAMTS2):​c.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC​(p.Pro33_Pro34insLeuLeuProProProProProLeuLeuProProProProPro) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 147,326 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 (★). Synonymous variant affecting the same amino acid position (i.e. P34P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000011 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

ADAMTS2
NM_014244.5 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP3
Nonframeshift variant in repetitive region in NM_014244.5

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADAMTS2NM_014244.5 linkc.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC p.Pro33_Pro34insLeuLeuProProProProProLeuLeuProProProProPro conservative_inframe_insertion Exon 1 of 22 ENST00000251582.12 NP_055059.2 O95450-1
ADAMTS2NM_021599.4 linkc.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC p.Pro33_Pro34insLeuLeuProProProProProLeuLeuProProProProPro conservative_inframe_insertion Exon 1 of 11 NP_067610.1 O95450-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADAMTS2ENST00000251582.12 linkc.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC p.Pro33_Pro34insLeuLeuProProProProProLeuLeuProProProProPro conservative_inframe_insertion Exon 1 of 22 1 NM_014244.5 ENSP00000251582.7 O95450-1
ADAMTS2ENST00000274609.5 linkc.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC p.Pro33_Pro34insLeuLeuProProProProProLeuLeuProProProProPro conservative_inframe_insertion Exon 1 of 11 1 ENSP00000274609.5 O95450-2
ADAMTS2ENST00000518335.3 linkc.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC p.Pro33_Pro34insLeuLeuProProProProProLeuLeuProProProProPro conservative_inframe_insertion Exon 1 of 21 3 ENSP00000489888.2 A0A1B0GTY3
ADAMTS2ENST00000698889.1 linkn.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC non_coding_transcript_exon_variant Exon 1 of 21 ENSP00000514008.1 A0A8V8TMU7

Frequencies

GnomAD3 genomes
AF:
0.0000136
AC:
2
AN:
147326
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000300
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000107
AC:
1
AN:
934818
Hom.:
0
Cov.:
30
AF XY:
0.00000225
AC XY:
1
AN XY:
445130
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
18142
American (AMR)
AF:
0.00
AC:
0
AN:
4576
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
8554
East Asian (EAS)
AF:
0.00
AC:
0
AN:
12708
South Asian (SAS)
AF:
0.00
AC:
0
AN:
18024
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
12438
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
2244
European-Non Finnish (NFE)
AF:
0.00000121
AC:
1
AN:
824070
Other (OTH)
AF:
0.00
AC:
0
AN:
34062
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000136
AC:
2
AN:
147326
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
71752
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
40190
American (AMR)
AF:
0.00
AC:
0
AN:
14908
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3418
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5000
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4716
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
9278
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
308
European-Non Finnish (NFE)
AF:
0.0000300
AC:
2
AN:
66570
Other (OTH)
AF:
0.00
AC:
0
AN:
2026
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Uncertain:1
Mar 15, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant, c.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC, results in the insertion of 14 amino acid(s) of the ADAMTS2 protein (p.Pro33_Pro34insLeuLeuProProProProProLeuLeuProProProProPro), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
3.2
Mutation Taster
=85/15
polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1064794627; hg19: chr5-178772229; API