rs34424371

Positions:

chr5-179154150-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000251582.12(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
ENST00000251582.12 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.335

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein
ADAMTS2	NM_014244.5 linkuse as main transcript	c.1281C>T	p.Asp427=	synonymous_variant	8/22	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4 linkuse as main transcript	c.1281C>T	p.Asp427=	synonymous_variant	8/11		NP_067610.1
ADAMTS2	XM_047417895.1 linkuse as main transcript	c.786C>T	p.Asp262=	synonymous_variant	7/21		XP_047273851.1
ADAMTS2	XM_047417896.1 linkuse as main transcript	c.399C>T	p.Asp133=	synonymous_variant	6/20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12 linkuse as main transcript	c.1281C>T	p.Asp427=	synonymous_variant	8/22	1	NM_014244.5	ENSP00000251582	P2	O95450-1
ADAMTS2	ENST00000274609.5 linkuse as main transcript	c.1281C>T	p.Asp427=	synonymous_variant	8/11	1		ENSP00000274609		O95450-2
ADAMTS2	ENST00000518335.3 linkuse as main transcript	c.1281C>T	p.Asp427=	synonymous_variant	8/21	3		ENSP00000489888	A2
ADAMTS2	ENST00000698889.1 linkuse as main transcript	c.1281C>T	p.Asp427=	synonymous_variant, NMD_transcript_variant	8/21			ENSP00000514008

Frequencies

GnomAD3 genomes

AF:

0.0243

AC:

3704

AN:

152184

Hom.:

149

Cov.:

show subpopulations

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.:

AF XY:

0.00519

AC XY:

534

AN XY:

102902

show subpopulations

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.:

AF XY:

0.00247

AC XY:

1748

AN XY:

707492

show subpopulations

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.:

AF XY:

0.0238

AC XY:

1775

AN XY:

74480

show subpopulations

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.:

Bravo

AF:

0.0282

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 22, 2015	- -
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	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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over