5-179345228-GGCGGCGGCGGCGGCGGCAGGA-GGCGGCGGCGGCGGCGGCAGGAGCGGCGGCGGCGGCGGCAGGAGCGGCGGCGGCGGCGGCAGGA

Position:

• chr5-179345228-GGCGGCGGCGGCGGCGGCAGGA-GGCGGCGGCGGCGGCGGCAGGAGCGGCGGCGGCGGCGGCAGGAGCGGCGGCGGCGGCGGCAGGA

Variant summary

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

The NM_014244.5(ADAMTS2):​c.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC​(p.Pro33_Pro34insLeuLeuProProProProProLeuLeuProProProProPro) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 147,326 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADAMTS2 NM_014244.5 conservative_inframe_insertion
• 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	Protein	UniProt
ADAMTS2	NM_014244.5	c.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC	p.Pro33_Pro34insLeuLeuProProProProProLeuLeuProProProProPro	conservative_inframe_insertion	1/22	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4	c.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC	p.Pro33_Pro34insLeuLeuProProProProProLeuLeuProProProProPro	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.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC	p.Pro33_Pro34insLeuLeuProProProProProLeuLeuProProProProPro	conservative_inframe_insertion	1/22	1	NM_014244.5	ENSP00000251582.7
ADAMTS2	ENST00000274609.5	c.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC	p.Pro33_Pro34insLeuLeuProProProProProLeuLeuProProProProPro	conservative_inframe_insertion	1/11	1		ENSP00000274609.5
ADAMTS2	ENST00000518335.3	c.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC	p.Pro33_Pro34insLeuLeuProProProProProLeuLeuProProProProPro	conservative_inframe_insertion	1/21	3		ENSP00000489888.2
ADAMTS2	ENST00000698889.1	n.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC		non_coding_transcript_exon_variant	1/21			ENSP00000514008.1

Frequencies

GnomAD3 genomes AF: 0.0000136 AC: 2 AN: 147326 Hom.: 0 Cov.: 33

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: 0.0000300

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000107 AC: 1 AN: 934818 Hom.: 0 Cov.: 30 AF XY: 0.00000225 AC XY: 1 AN XY: 445130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000121

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000136 AC: 2 AN: 147326 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 71752

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: 0.0000300

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

Labcorp Genetics (formerly Invitae), Labcorp

Mar 15, 2022

This variant, c.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC, results in the insertion of 14 amino acid(s) of the ADAMTS2 protein (p.Pro33_Pro34insLeuLeuProProProProProLeuLeuProProProProPro), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). 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. -

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: rs1064794627; hg19: chr5-178772229;