rs1054480

Positions:

chr5-179113974-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014244.5(ADAMTS2):c.3529C>T(p.Pro1177Ser) variant causes a missense change. The variant allele was found at a frequency of 0.291 in 1,613,916 control chromosomes in the GnomAD database, including 71,235 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 5426 hom., cov: 32)

Exomes 𝑓: 0.30 ( 65809 hom. )

Consequence

ADAMTS2
NM_014244.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.99

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004896581).

BP6

Variant 5-179113974-G-A is Benign according to our data. Variant chr5-179113974-G-A is described in ClinVar as [Benign]. Clinvar id is 353083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179113974-G-A is described in Lovd as [Benign].

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
ADAMTS2	NM_014244.5 linkuse as main transcript	c.3529C>T	p.Pro1177Ser	missense_variant	22/22	ENST00000251582.12	NP_055059.2
ADAMTS2	XM_047417895.1 linkuse as main transcript	c.3034C>T	p.Pro1012Ser	missense_variant	21/21		XP_047273851.1
ADAMTS2	XM_047417896.1 linkuse as main transcript	c.2647C>T	p.Pro883Ser	missense_variant	20/20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12 linkuse as main transcript	c.3529C>T	p.Pro1177Ser	missense_variant	22/22	1	NM_014244.5	ENSP00000251582	P2	O95450-1

Frequencies

GnomAD3 genomes

AF:

0.245

AC:

37273

AN:

151918

Hom.:

5425

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0806

Gnomad AMI

AF:

0.433

Gnomad AMR

AF:

0.352

Gnomad ASJ

AF:

0.312

Gnomad EAS

AF:

0.319

Gnomad SAS

AF:

0.376

Gnomad FIN

AF:

0.285

Gnomad MID

AF:

0.325

Gnomad NFE

AF:

0.294

Gnomad OTH

AF:

0.277

GnomAD3 exomes

AF:

0.308

AC:

77472

AN:

251482

Hom.:

12671

AF XY:

0.312

AC XY:

42391

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0739

Gnomad AMR exome

AF:

0.408

Gnomad ASJ exome

AF:

0.312

Gnomad EAS exome

AF:

0.319

Gnomad SAS exome

AF:

0.371

Gnomad FIN exome

AF:

0.292

Gnomad NFE exome

AF:

0.295

Gnomad OTH exome

AF:

0.311

GnomAD4 exome

AF:

0.295

AC:

431642

AN:

1461880

Hom.:

65809

Cov.:

AF XY:

0.298

AC XY:

217028

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0723

Gnomad4 AMR exome

AF:

0.403

Gnomad4 ASJ exome

AF:

0.310

Gnomad4 EAS exome

AF:

0.356

Gnomad4 SAS exome

AF:

0.368

Gnomad4 FIN exome

AF:

0.288

Gnomad4 NFE exome

AF:

0.290

Gnomad4 OTH exome

AF:

0.287

GnomAD4 genome

AF:

0.245

AC:

37282

AN:

152036

Hom.:

5426

Cov.:

AF XY:

0.248

AC XY:

18432

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.0807

Gnomad4 AMR

AF:

0.353

Gnomad4 ASJ

AF:

0.312

Gnomad4 EAS

AF:

0.319

Gnomad4 SAS

AF:

0.373

Gnomad4 FIN

AF:

0.285

Gnomad4 NFE

AF:

0.294

Gnomad4 OTH

AF:

0.274

Alfa

AF:

0.290

Hom.:

16260

Bravo

AF:

0.243

TwinsUK

AF:

0.297

AC:

1102

ALSPAC

AF:

0.280

AC:

1081

ESP6500AA

AF:

0.0810

AC:

357

ESP6500EA

AF:

0.294

AC:

2527

ExAC

AF:

0.300

AC:

36398

Asia WGS

AF:

0.314

AC:

1093

AN:

3478

EpiCase

AF:

0.305

EpiControl

AF:

0.301

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type

Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Feb 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 07, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

Eigen

Benign

-0.098

Eigen_PC

Benign

0.0069

FATHMM_MKL

Uncertain

0.91

MetaRNN

Benign

0.0049

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.0

MutationTaster

Benign

0.78

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.58

REVEL

Benign

0.10

Sift

Benign

0.13

Sift4G

Benign

0.94

Polyphen

0.65

Vest4

0.053

MPC

0.41

ClinPred

0.030

GERP RS

5.0

Varity_R

0.075

gMVP

0.18

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

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