5-179345227-GGGCGGC-GGGC

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP3

The NM_014244.5(ADAMTS2):c.99_101del(p.Pro34del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000355 in 1,107,268 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P33P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: ADAMTS2 NM_014244.5 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_014244.5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS2	NM_014244.5	c.99_101del	p.Pro34del	inframe_deletion	1/22	ENST00000251582.12
ADAMTS2	NM_021599.4	c.99_101del	p.Pro34del	inframe_deletion	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.99_101del	p.Pro34del	inframe_deletion	1/22	1	NM_014244.5	P2
ADAMTS2	ENST00000274609.5	c.99_101del	p.Pro34del	inframe_deletion	1/11	1
ADAMTS2	ENST00000518335.3	c.99_101del	p.Pro34del	inframe_deletion	1/21	3		A2
ADAMTS2	ENST00000698889.1	c.99_101del	p.Pro34del	inframe_deletion, NMD_transcript_variant	1/21

Frequencies

GnomAD3 genomes AF: 0.0000405 AC: 6 AN: 148168 Hom.: 0 Cov.: 32

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: 0.0000899

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00267 AC: 2 AN: 748 Hom.: 0 AF XY: 0.00235 AC XY: 1 AN XY: 426

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0385

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: 0.00186

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000404 AC: 387 AN: 958998 Hom.: 0 AF XY: 0.000468 AC XY: 214 AN XY: 457294

Gnomad4 AFR exome AF: 0.000268

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00174

Gnomad4 EAS exome AF: 0.00214

Gnomad4 SAS exome AF: 0.000109

Gnomad4 FIN exome AF: 0.00200

Gnomad4 NFE exome AF: 0.000317

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.0000405 AC: 6 AN: 148270 Hom.: 0 Cov.: 32 AF XY: 0.0000415 AC XY: 3 AN XY: 72274

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000899

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 25, 2022

This variant, c.99_101del, results in the deletion of 1 amino acid(s) of the ADAMTS2 protein (p.Pro34del), 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 poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ADAMTS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 469681). 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

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: rs770212030; hg19: chr5-178772228;