rs763392299

Positions:

• chr5-179345249-AGCG-A
• chr5-179345249-AGCG-AGCGGCG
• chr5-179345249-AGCG-AGCGGCGGCG

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014244.5(ADAMTS2):​c.77_79del​(p.Pro26del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000834 in 995,228 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: ADAMTS2 NM_014244.5 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.33

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.77_79del	p.Pro26del	inframe_deletion	1/22	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4	c.77_79del	p.Pro26del	inframe_deletion	1/11		NP_067610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.77_79del	p.Pro26del	inframe_deletion	1/22	1	NM_014244.5	ENSP00000251582	P2
ADAMTS2	ENST00000274609.5	c.77_79del	p.Pro26del	inframe_deletion	1/11	1		ENSP00000274609
ADAMTS2	ENST00000518335.3	c.77_79del	p.Pro26del	inframe_deletion	1/21	3		ENSP00000489888	A2
ADAMTS2	ENST00000698889.1	c.77_79del	p.Pro26del	inframe_deletion, NMD_transcript_variant	1/21			ENSP00000514008

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00171 AC: 2 AN: 1168 Hom.: 0 AF XY: 0.00149 AC XY: 1 AN XY: 672

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00273

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000834 AC: 83 AN: 995228 Hom.: 0 AF XY: 0.0000799 AC XY: 38 AN XY: 475304

Gnomad4 AFR exome AF: 0.0000513

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.000101

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000522

Gnomad4 FIN exome AF: 0.000128

Gnomad4 NFE exome AF: 0.0000851

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2021	This variant, c.77_79del, results in the deletion of 1 amino acid(s) of the ADAMTS2 protein (p.Pro26del), 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 26, 2020	- -

Ehlers-Danlos syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs763392299; hg19: chr5-178772250;