rs117222015

Positions:

chr5-179207640-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014244.5(ADAMTS2):c.764G>A(p.Arg255Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,613,770 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00085 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0011 ( 13 hom. )

Consequence

ADAMTS2
NM_014244.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.601

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=0.0038357973).

BP6

Variant 5-179207640-C-T is Benign according to our data. Variant chr5-179207640-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 353132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179207640-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000853 (130/152342) while in subpopulation EAS AF= 0.0081 (42/5184). AF 95% confidence interval is 0.00616. There are 1 homozygotes in gnomad4. There are 70 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS2	NM_014244.5 linkuse as main transcript	c.764G>A	p.Arg255Gln	missense_variant	4/22	ENST00000251582.12	NP_055059.2	O95450-1
ADAMTS2	NM_021599.4 linkuse as main transcript	c.764G>A	p.Arg255Gln	missense_variant	4/11		NP_067610.1	O95450-2
ADAMTS2	XM_047417895.1 linkuse as main transcript	c.269G>A	p.Arg90Gln	missense_variant	3/21		XP_047273851.1
ADAMTS2	XM_047417896.1 linkuse as main transcript	c.-119G>A		5_prime_UTR_variant	2/20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ADAMTS2	ENST00000251582.12 linkuse as main transcript	c.764G>A	p.Arg255Gln	missense_variant	4/22	1	NM_014244.5	ENSP00000251582.7	O95450-1
ADAMTS2	ENST00000274609.5 linkuse as main transcript	c.764G>A	p.Arg255Gln	missense_variant	4/11	1		ENSP00000274609.5	O95450-2
ADAMTS2	ENST00000518335.3 linkuse as main transcript	c.764G>A	p.Arg255Gln	missense_variant	4/21	3		ENSP00000489888.2	A0A1B0GTY3
ADAMTS2	ENST00000698889.1 linkuse as main transcript	n.764G>A		non_coding_transcript_exon_variant	4/21			ENSP00000514008.1	A0A8V8TMU7

Frequencies

GnomAD3 genomes

AF:

0.000854

AC:

130

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00808

Gnomad SAS

AF:

0.00807

Gnomad FIN

AF:

0.000658

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00202

AC:

508

AN:

251320

Hom.:

AF XY:

0.00218

AC XY:

296

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000520

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00936

Gnomad SAS exome

AF:

0.00797

Gnomad FIN exome

AF:

0.000694

Gnomad NFE exome

AF:

0.000422

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00111

AC:

1625

AN:

1461428

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

927

AN XY:

727028

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0101

Gnomad4 SAS exome

AF:

0.00738

Gnomad4 FIN exome

AF:

0.000604

Gnomad4 NFE exome

AF:

0.000415

Gnomad4 OTH exome

AF:

0.00104

GnomAD4 genome

AF:

0.000853

AC:

130

AN:

152342

Hom.:

Cov.:

AF XY:

0.000940

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00810

Gnomad4 SAS

AF:

0.00808

Gnomad4 FIN

AF:

0.000658

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000721

Hom.:

Bravo

AF:

0.000676

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00226

AC:

274

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 21, 2019	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ADAMTS2: BP4, BS2 -

ADAMTS2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Ehlers-Danlos syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 17, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.56

CADD

Benign

7.9

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

T;.;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.087

MetaRNN

Benign

0.0038

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;.;L

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.98

N;.;N

REVEL

Benign

0.025

Sift

Benign

0.12

T;.;T

Sift4G

Benign

0.063

T;.;T

Polyphen

0.0010

B;.;B

Vest4

0.094

MVP

0.32

MPC

0.47

ClinPred

0.011

GERP RS

3.5

Varity_R

0.028

gMVP

0.33

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