5-179345258-GGCAGCAGCAGCA-GGCAGCAGCAGCAGCAGCAGCAGCAGCA

Position:

• chr5-179345258-GGCAGCAGCAGCA-GGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_014244.5(ADAMTS2):​c.70_71insTGCTGCTGCTGCTGC​(p.Leu19_Leu23dup) variant causes a 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. 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 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.00

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.70_71insTGCTGCTGCTGCTGC	p.Leu19_Leu23dup	inframe_insertion	1/22	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4	c.70_71insTGCTGCTGCTGCTGC	p.Leu19_Leu23dup	inframe_insertion	1/11		NP_067610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.70_71insTGCTGCTGCTGCTGC	p.Leu19_Leu23dup	inframe_insertion	1/22	1	NM_014244.5	ENSP00000251582	P2
ADAMTS2	ENST00000274609.5	c.70_71insTGCTGCTGCTGCTGC	p.Leu19_Leu23dup	inframe_insertion	1/11	1		ENSP00000274609
ADAMTS2	ENST00000518335.3	c.70_71insTGCTGCTGCTGCTGC	p.Leu19_Leu23dup	inframe_insertion	1/21	3		ENSP00000489888	A2
ADAMTS2	ENST00000698889.1	c.70_71insTGCTGCTGCTGCTGC	p.Leu19_Leu23dup	inframe_insertion, NMD_transcript_variant	1/21			ENSP00000514008

Frequencies

GnomAD3 genomes AF: 0.0000204 AC: 3 AN: 146980 Hom.: 0 Cov.: 28

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: 21 AN: 989358 Hom.: 0 Cov.: 29 AF XY: 0.0000233 AC XY: 11 AN XY: 472146

Gnomad4 AFR exome AF: 0.000105

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000315

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000204 AC: 3 AN: 147072 Hom.: 0 Cov.: 28 AF XY: 0.0000279 AC XY: 2 AN XY: 71648

Gnomad4 AFR AF: 0.0000250

Gnomad4 AMR AF: 0.000134

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 17, 2021

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

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jan 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs568040559; hg19: chr5-178772259;