5-179110916-C-T

Position:

• chr5-179110916-C-T

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.*2951G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 151,976 control chromosomes in the GnomAD database, including 5,392 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (5392 hom., cov: 33)
  • Exomes 𝑓: 0.50 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADAMTS2 NM_014244.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0490

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=-0.71).
• BP6: Variant 5-179110916-C-T is Benign according to our data. Variant chr5-179110916-C-T is described in ClinVar as [Benign]. Clinvar id is 353036.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.*2951G>A		3_prime_UTR_variant	22/22	ENST00000251582.12	NP_055059.2
ADAMTS2	XM_047417895.1	c.*2951G>A		3_prime_UTR_variant	21/21		XP_047273851.1
ADAMTS2	XM_047417896.1	c.*2951G>A		3_prime_UTR_variant	20/20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.*2951G>A		3_prime_UTR_variant	22/22	1	NM_014244.5	ENSP00000251582	P2

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37274 AN: 151858 Hom.: 5390 Cov.: 33

Gnomad AFR AF: 0.0811

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.316

Gnomad SAS AF: 0.376

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.278

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.500 AC: 1 AN: 2 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

Gnomad4 NFE exome AF: 0.500

GnomAD4 genome AF: 0.245 AC: 37284 AN: 151976 Hom.: 5392 Cov.: 33 AF XY: 0.248 AC XY: 18418 AN XY: 74270

Gnomad4 AFR AF: 0.0812

Gnomad4 AMR AF: 0.352

Gnomad4 ASJ AF: 0.319

Gnomad4 EAS AF: 0.316

Gnomad4 SAS AF: 0.374

Gnomad4 FIN AF: 0.282

Gnomad4 NFE AF: 0.294

Gnomad4 OTH AF: 0.275

Alfa AF: 0.274 Hom.: 1243

Bravo AF: 0.244

Asia WGS AF: 0.314 AC: 1095 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	-0.71
CADD	Benign	13
DANN	Benign	0.82

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: rs1044205; hg19: chr5-178537917;