rs34424371

chr5-179154150-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014244.5(ADAMTS2):c.1281C>T(p.Asp427=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00487 in 1,578,486 control chromosomes in the GnomAD database, including 316 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (151 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (165 hom.)
• Consequence: ADAMTS2 NM_014244.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.335

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 5-179154150-G-A is Benign according to our data. Variant chr5-179154150-G-A is described in ClinVar as [Benign]. Clinvar id is 198855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179154150-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.335 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0804 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS2	NM_014244.5	c.1281C>T	p.Asp427=	synonymous_variant	8/22	ENST00000251582.12
ADAMTS2	NM_021599.4	c.1281C>T	p.Asp427=	synonymous_variant	8/11
ADAMTS2	XM_047417895.1	c.786C>T	p.Asp262=	synonymous_variant	7/21
ADAMTS2	XM_047417896.1	c.399C>T	p.Asp133=	synonymous_variant	6/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.1281C>T	p.Asp427=	synonymous_variant	8/22	1	NM_014244.5	P2
ADAMTS2	ENST00000274609.5	c.1281C>T	p.Asp427=	synonymous_variant	8/11	1
ADAMTS2	ENST00000518335.3	c.1281C>T	p.Asp427=	synonymous_variant	8/21	3		A2
ADAMTS2	ENST00000698889.1	c.1281C>T	p.Asp427=	synonymous_variant, NMD_transcript_variant	8/21

Frequencies

GnomAD3 genomes AF: 0.0243 AC: 3704 AN: 152184 Hom.: 149 Cov.: 33

Gnomad AFR AF: 0.0827

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.00707 AC: 1337 AN: 189034 Hom.: 44 AF XY: 0.00519 AC XY: 534 AN XY: 102902

Gnomad AFR exome AF: 0.0842

Gnomad AMR exome AF: 0.00786

Gnomad ASJ exome AF: 0.000334

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000351

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000312

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00278 AC: 3966 AN: 1426184 Hom.: 165 Cov.: 32 AF XY: 0.00247 AC XY: 1748 AN XY: 707492

Gnomad4 AFR exome AF: 0.0884

Gnomad4 AMR exome AF: 0.00915

Gnomad4 ASJ exome AF: 0.000156

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000292

Gnomad4 FIN exome AF: 0.0000248

Gnomad4 NFE exome AF: 0.000214

Gnomad4 OTH exome AF: 0.00626

GnomAD4 genome AF: 0.0244 AC: 3714 AN: 152302 Hom.: 151 Cov.: 33 AF XY: 0.0238 AC XY: 1775 AN XY: 74480

Gnomad4 AFR AF: 0.0827

Gnomad4 AMR AF: 0.0137

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0122 Hom.: 23

Bravo AF: 0.0282

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 30, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Ehlers-Danlos syndrome, dermatosparaxis type Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	-0.53
Cadd	Benign	8.5
Dann	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34424371; hg19: chr5-178581151;