5-179236407-A-C

Variant names:

• chr5-179236407-A-C
• rs469568
• NM_014244.5:c.689-28692T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014244.5(ADAMTS2):​c.689-28692T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.534 in 152,068 control chromosomes in the GnomAD database, including 22,928 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.53 (22928 hom., cov: 32)
• Consequence: ADAMTS2 NM_014244.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.553
• Publications: 13 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

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.689-28692T>G		intron	N/A	NP_055059.2
	ADAMTS2	NM_021599.4		c.689-28692T>G		intron	N/A	NP_067610.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.689-28692T>G		intron	N/A	ENSP00000251582.7
	ADAMTS2	ENST00000274609.5	TSL:1	c.689-28692T>G		intron	N/A	ENSP00000274609.5
	ADAMTS2	ENST00000518335.3	TSL:3	c.689-28692T>G		intron	N/A	ENSP00000489888.2

Frequencies

GnomAD3 genomes AF: 0.535 AC: 81228 AN: 151950 Hom.: 22909 Cov.: 32

Gnomad AFR AF: 0.592

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.549

Gnomad EAS AF: 0.0529

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.701

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.526

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.534 AC: 81277 AN: 152068 Hom.: 22928 Cov.: 32 AF XY: 0.533 AC XY: 39634 AN XY: 74330

African (AFR) AF: 0.592 AC: 24523 AN: 41426

American (AMR) AF: 0.411 AC: 6289 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 1903 AN: 3468

East Asian (EAS) AF: 0.0528 AC: 274 AN: 5188

South Asian (SAS) AF: 0.344 AC: 1657 AN: 4818

European-Finnish (FIN) AF: 0.701 AC: 7418 AN: 10584

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.552 AC: 37543 AN: 67978

Other (OTH) AF: 0.519 AC: 1095 AN: 2108

Alfa AF: 0.532 Hom.: 44492

Bravo AF: 0.513

Asia WGS AF: 0.245 AC: 853 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	5.7
DANN	Benign	0.81
PhyloP100		0.55
Mutation Taster		=100/0	polymorphism (auto)

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: rs469568; hg19: chr5-178663408;