5-179111428-G-A

Position:

• chr5-179111428-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014244.5(ADAMTS2):​c.*2439C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0407 in 152,380 control chromosomes in the GnomAD database, including 167 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.041 (167 hom., cov: 33)
  • Exomes 𝑓: 0.045 (0 hom.)
• Consequence: ADAMTS2 NM_014244.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.289

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 5-179111428-G-A is Benign according to our data. Variant chr5-179111428-G-A is described in ClinVar as [Benign]. Clinvar id is 353047.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS2	NM_014244.5	c.*2439C>T		3_prime_UTR_variant	22/22	ENST00000251582.12
ADAMTS2	XM_047417895.1	c.*2439C>T		3_prime_UTR_variant	21/21
ADAMTS2	XM_047417896.1	c.*2439C>T		3_prime_UTR_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.*2439C>T		3_prime_UTR_variant	22/22	1	NM_014244.5	P2

Frequencies

GnomAD3 genomes AF: 0.0407 AC: 6201 AN: 152218 Hom.: 168 Cov.: 33

Gnomad AFR AF: 0.00914

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.0476

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00806

Gnomad FIN AF: 0.0434

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0620

Gnomad OTH AF: 0.0487

GnomAD4 exome AF: 0.0455 AC: 2 AN: 44 Hom.: 0 Cov.: 0 AF XY: 0.0625 AC XY: 2 AN XY: 32

Gnomad4 AFR exome AF: 0.00

Gnomad4 NFE exome AF: 0.0526

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0407 AC: 6199 AN: 152336 Hom.: 167 Cov.: 33 AF XY: 0.0381 AC XY: 2838 AN XY: 74490

Gnomad4 AFR AF: 0.00912

Gnomad4 AMR AF: 0.0475

Gnomad4 ASJ AF: 0.0467

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00807

Gnomad4 FIN AF: 0.0434

Gnomad4 NFE AF: 0.0620

Gnomad4 OTH AF: 0.0482

Alfa AF: 0.0394 Hom.: 39

Bravo AF: 0.0405

Asia WGS AF: 0.00722 AC: 26 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.7
DANN	Benign	0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs78886769; hg19: chr5-178538429;