5-179111471-G-A

Position:

• chr5-179111471-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.*2396C>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 0.308 in 152,164 control chromosomes in the GnomAD database, including 7,297 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.31 (7296 hom., cov: 33)
  • Exomes 𝑓: 0.33 (1 hom.)
• Consequence: ADAMTS2 NM_014244.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.689

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=-0.89).
• BP6: Variant 5-179111471-G-A is Benign according to our data. Variant chr5-179111471-G-A is described in ClinVar as [Benign]. Clinvar id is 353048.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS2	NM_014244.5	c.*2396C>T		3_prime_UTR_variant	22/22	ENST00000251582.12
ADAMTS2	XM_047417895.1	c.*2396C>T		3_prime_UTR_variant	21/21
ADAMTS2	XM_047417896.1	c.*2396C>T		3_prime_UTR_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.*2396C>T		3_prime_UTR_variant	22/22	1	NM_014244.5	P2

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46881 AN: 152028 Hom.: 7293 Cov.: 33

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.312

GnomAD4 exome AF: 0.333 AC: 6 AN: 18 Hom.: 1 Cov.: 0 AF XY: 0.333 AC XY: 6 AN XY: 18

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.167

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.308 AC: 46904 AN: 152146 Hom.: 7296 Cov.: 33 AF XY: 0.311 AC XY: 23142 AN XY: 74372

Gnomad4 AFR AF: 0.328

Gnomad4 AMR AF: 0.265

Gnomad4 ASJ AF: 0.252

Gnomad4 EAS AF: 0.407

Gnomad4 SAS AF: 0.341

Gnomad4 FIN AF: 0.345

Gnomad4 NFE AF: 0.294

Gnomad4 OTH AF: 0.317

Alfa AF: 0.296 Hom.: 3299

Bravo AF: 0.301

Asia WGS AF: 0.403 AC: 1399 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	-0.89
CADD	Benign	1.2
DANN	Benign	0.84

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: rs3797615; hg19: chr5-178538472;