5-179345228-GGCGGCGGCGGCGGCGGCAGGA-GGCGGCGGCGGCGGCGGCAGGAGCGGCGGCGGCGGCGGCAGGA
Variant summary
Our verdict is Benign. Variant got -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. Variant has been reported in ClinVar 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
NM_014244.5 conservative_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.24
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ADAMTS2 | NM_014244.5 | c.80_100dupTCCTGCCGCCGCCGCCGCCGC | p.Leu27_Pro33dup | conservative_inframe_insertion | 1/22 | ENST00000251582.12 | NP_055059.2 | |
ADAMTS2 | NM_021599.4 | c.80_100dupTCCTGCCGCCGCCGCCGCCGC | p.Leu27_Pro33dup | conservative_inframe_insertion | 1/11 | NP_067610.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ADAMTS2 | ENST00000251582.12 | c.80_100dupTCCTGCCGCCGCCGCCGCCGC | p.Leu27_Pro33dup | conservative_inframe_insertion | 1/22 | 1 | NM_014244.5 | ENSP00000251582.7 | ||
ADAMTS2 | ENST00000274609.5 | c.80_100dupTCCTGCCGCCGCCGCCGCCGC | p.Leu27_Pro33dup | conservative_inframe_insertion | 1/11 | 1 | ENSP00000274609.5 | |||
ADAMTS2 | ENST00000518335.3 | c.80_100dupTCCTGCCGCCGCCGCCGCCGC | p.Leu27_Pro33dup | conservative_inframe_insertion | 1/21 | 3 | ENSP00000489888.2 | |||
ADAMTS2 | ENST00000698889.1 | n.80_100dupTCCTGCCGCCGCCGCCGCCGC | non_coding_transcript_exon_variant | 1/21 | ENSP00000514008.1 |
Frequencies
GnomAD3 genomes AF: 0.00538 AC: 793AN: 147288Hom.: 3 Cov.: 33
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GnomAD3 exomes AF: 0.00683 AC: 5AN: 732Hom.: 0 AF XY: 0.00242 AC XY: 1AN XY: 414
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00250 AC: 2318AN: 928860Hom.: 7 Cov.: 30 AF XY: 0.00246 AC XY: 1090AN XY: 442302
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GnomAD4 genome AF: 0.00538 AC: 793AN: 147388Hom.: 3 Cov.: 33 AF XY: 0.00507 AC XY: 364AN XY: 71848
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ehlers-Danlos syndrome, dermatosparaxis type Benign:2
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 20, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 03, 2025 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | ADAMTS2: BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 10, 2024 | See Variant Classification Assertion Criteria. - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 10, 2019 | Variant summary: ADAMTS2 c.80_100dup21 (p.Leu27_Pro33dup) results in an in-frame duplication of 7 amino acids into the encoded protein. The variant allele was found at a frequency of 0.0044 in 27980 control chromosomes. The observed variant frequency is approximately 1.5 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 benign. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2x VUS, 1x Benign). Based on the evidence outlined above, the variant was classified as benign. - |
Ehlers-Danlos syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Mar 15, 2022 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at