5-179345258-GGCAGCAGCAGCAGCA-GGCA

Variant names:

• chr5-179345258-GGCAGCAGCAGCA-G
• rs568040559
• NM_014244.5:c.59_70delTGCTGCTGCTGC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_014244.5(ADAMTS2):​c.59_70delTGCTGCTGCTGC​(p.Leu20_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 0.00000352 in 1,136,334 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L20L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: ADAMTS2 NM_014244.5 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.38
• Publications: 6 publications found

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]

ADAMTS2 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, dermatosparaxis type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P, PanelApp Australia, Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.59_70delTGCTGCTGCTGC	p.Leu20_Leu23del	disruptive_inframe_deletion	Exon 1 of 22	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4	c.59_70delTGCTGCTGCTGC	p.Leu20_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.59_70delTGCTGCTGCTGC	p.Leu20_Leu23del	disruptive_inframe_deletion	Exon 1 of 22	1	NM_014244.5	ENSP00000251582.7
ADAMTS2	ENST00000274609.5	c.59_70delTGCTGCTGCTGC	p.Leu20_Leu23del	disruptive_inframe_deletion	Exon 1 of 11	1		ENSP00000274609.5
ADAMTS2	ENST00000518335.3	c.59_70delTGCTGCTGCTGC	p.Leu20_Leu23del	disruptive_inframe_deletion	Exon 1 of 21	3		ENSP00000489888.2
ADAMTS2	ENST00000698889.1	n.59_70delTGCTGCTGCTGC		non_coding_transcript_exon_variant	Exon 1 of 21			ENSP00000514008.1

Frequencies

GnomAD3 genomes AF: 0.00000680 AC: 1 AN: 146980 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000250

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000303 AC: 3 AN: 989354 Hom.: 0 AF XY: 0.00000424 AC XY: 2 AN XY: 472146

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 19040

American (AMR) AF: 0.00 AC: 0 AN: 5490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9740

East Asian (EAS) AF: 0.00 AC: 0 AN: 15854

South Asian (SAS) AF: 0.00 AC: 0 AN: 18838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2440

European-Non Finnish (NFE) AF: 0.00000346 AC: 3 AN: 865852

Other (OTH) AF: 0.00 AC: 0 AN: 36820

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000680 AC: 1 AN: 146980 Hom.: 0 Cov.: 28 AF XY: 0.0000140 AC XY: 1 AN XY: 71540

African (AFR) AF: 0.0000250 AC: 1 AN: 39970

American (AMR) AF: 0.00 AC: 0 AN: 14908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3404

East Asian (EAS) AF: 0.00 AC: 0 AN: 4958

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 298

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66392

Other (OTH) AF: 0.00 AC: 0 AN: 2042

Alfa AF: 0.00 Hom.: 36

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.4
Mutation Taster		=162/38	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs568040559; hg19: chr5-178772259;