5-179345227-GGGCGGCGGC-GGGCGGC

Variant names:

• chr5-179345227-GGGC-G
• rs770212030
• NM_014244.5:c.99_101delGCC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_014244.5(ADAMTS2):​c.99_101delGCC​(p.Pro34del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000355 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 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24
• Publications: 2 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: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_014244.5

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014244.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	NM_014244.5	MANE Select	c.99_101delGCC	p.Pro34del	disruptive_inframe_deletion	Exon 1 of 22	NP_055059.2
	ADAMTS2	NM_021599.4		c.99_101delGCC	p.Pro34del	disruptive_inframe_deletion	Exon 1 of 11	NP_067610.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.99_101delGCC	p.Pro34del	disruptive_inframe_deletion	Exon 1 of 22	ENSP00000251582.7
	ADAMTS2	ENST00000274609.5	TSL:1	c.99_101delGCC	p.Pro34del	disruptive_inframe_deletion	Exon 1 of 11	ENSP00000274609.5
	ADAMTS2	ENST00000518335.3	TSL:3	c.99_101delGCC	p.Pro34del	disruptive_inframe_deletion	Exon 1 of 21	ENSP00000489888.2

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

GnomAD2 exomes AF: 0.00267 AC: 2 AN: 748 AF XY: 0.00235

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 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

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

African (AFR) AF: 0.000268 AC: 5 AN: 18636

American (AMR) AF: 0.00181 AC: 9 AN: 4982

Ashkenazi Jewish (ASJ) AF: 0.00174 AC: 16 AN: 9214

East Asian (EAS) AF: 0.00214 AC: 30 AN: 14020

South Asian (SAS) AF: 0.000109 AC: 2 AN: 18266

European-Finnish (FIN) AF: 0.00200 AC: 28 AN: 13984

Middle Eastern (MID) AF: 0.00255 AC: 6 AN: 2352

European-Non Finnish (NFE) AF: 0.000317 AC: 267 AN: 842188

Other (OTH) AF: 0.000679 AC: 24 AN: 35356

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.00 AC: 0 AN: 40680

American (AMR) AF: 0.00 AC: 0 AN: 14972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3424

East Asian (EAS) AF: 0.00 AC: 0 AN: 5032

South Asian (SAS) AF: 0.00 AC: 0 AN: 4758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000899 AC: 6 AN: 66726

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Ehlers-Danlos syndrome, dermatosparaxis type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs770212030; hg19: chr5-178772228; COSMIC: COSV105860337;