5-179345258-GGCAGCAGCAGCA-GGCAGCA

Variant names:

• chr5-179345258-GGCAGCA-G
• rs568040559
• NM_014244.5:c.65_70delTGCTGC

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_014244.5(ADAMTS2):​c.65_70delTGCTGC​(p.Leu22_Leu23del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,136,060 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000075 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: ADAMTS2 NM_014244.5 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.65

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
• BP6: Variant 5-179345258-GGCAGCA-G is Benign according to our data. Variant chr5-179345258-GGCAGCA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 573576.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr5-179345258-GGCAGCA-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.65_70delTGCTGC	p.Leu22_Leu23del	disruptive_inframe_deletion	Exon 1 of 22	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4	c.65_70delTGCTGC	p.Leu22_Leu23del	disruptive_inframe_deletion	Exon 1 of 11		NP_067610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.65_70delTGCTGC	p.Leu22_Leu23del	disruptive_inframe_deletion	Exon 1 of 22	1	NM_014244.5	ENSP00000251582.7
ADAMTS2	ENST00000274609.5	c.65_70delTGCTGC	p.Leu22_Leu23del	disruptive_inframe_deletion	Exon 1 of 11	1		ENSP00000274609.5
ADAMTS2	ENST00000518335.3	c.65_70delTGCTGC	p.Leu22_Leu23del	disruptive_inframe_deletion	Exon 1 of 21	3		ENSP00000489888.2
ADAMTS2	ENST00000698889.1	n.65_70delTGCTGC		non_coding_transcript_exon_variant	Exon 1 of 21			ENSP00000514008.1

Frequencies

GnomAD3 genomes AF: 0.0000748 AC: 11 AN: 146980 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000175

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: 0.0000602

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000106 AC: 105 AN: 989080 Hom.: 0 AF XY: 0.000104 AC XY: 49 AN XY: 471984

Gnomad4 AFR exome AF: 0.000105

Gnomad4 AMR exome AF: 0.000182

Gnomad4 ASJ exome AF: 0.000103

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000531

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.0000815

GnomAD4 genome AF: 0.0000748 AC: 11 AN: 146980 Hom.: 0 Cov.: 28 AF XY: 0.000112 AC XY: 8 AN XY: 71540

Gnomad4 AFR AF: 0.000175

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: 0.0000602

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000604

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Uncertain:1

May 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.65_70del, results in the deletion of 2 amino acid(s) of the ADAMTS2 protein (p.Leu22_Leu23del), 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: 573576). 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 Benign:1

Apr 28, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;