chr5-179136001-C-T

Position:

chr5-179136001-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.1993G>A(p.Gly665Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,613,422 control chromosomes in the GnomAD database, including 187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0088 ( 11 hom., cov: 32)

Exomes 𝑓: 0.014 ( 176 hom. )

Consequence

ADAMTS2
NM_014244.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.13

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=0.0048826337).

BP6

Variant 5-179136001-C-T is Benign according to our data. Variant chr5-179136001-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 384810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179136001-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00877 (1335/152254) while in subpopulation NFE AF= 0.015 (1022/68018). AF 95% confidence interval is 0.0143. There are 11 homozygotes in gnomad4. There are 600 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS2	NM_014244.5 linkuse as main transcript	c.1993G>A	p.Gly665Arg	missense_variant	13/22	ENST00000251582.12	NP_055059.2	O95450-1
ADAMTS2	XM_047417895.1 linkuse as main transcript	c.1498G>A	p.Gly500Arg	missense_variant	12/21		XP_047273851.1
ADAMTS2	XM_047417896.1 linkuse as main transcript	c.1111G>A	p.Gly371Arg	missense_variant	11/20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ADAMTS2	ENST00000251582.12 linkuse as main transcript	c.1993G>A	p.Gly665Arg	missense_variant	13/22	1	NM_014244.5	ENSP00000251582.7	O95450-1
ADAMTS2	ENST00000518335.3 linkuse as main transcript	c.1993G>A	p.Gly665Arg	missense_variant	13/21	3		ENSP00000489888.2	A0A1B0GTY3
ADAMTS2	ENST00000698889.1 linkuse as main transcript	n.1993G>A		non_coding_transcript_exon_variant	13/21			ENSP00000514008.1	A0A8V8TMU7

Frequencies

GnomAD3 genomes

AF:

0.00878

AC:

1335

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00265

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.00458

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00782

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0150

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00779

AC:

1958

AN:

251246

Hom.:

AF XY:

0.00753

AC XY:

1023

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.00396

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00120

Gnomad SAS exome

AF:

0.00304

Gnomad FIN exome

AF:

0.00906

Gnomad NFE exome

AF:

0.0125

Gnomad OTH exome

AF:

0.00799

GnomAD4 exome

AF:

0.0135

AC:

19739

AN:

1461168

Hom.:

176

Cov.:

AF XY:

0.0132

AC XY:

9598

AN XY:

726886

show subpopulations

Gnomad4 AFR exome

AF:

0.00209

Gnomad4 AMR exome

AF:

0.00398

Gnomad4 ASJ exome

AF:

0.000803

Gnomad4 EAS exome

AF:

0.00106

Gnomad4 SAS exome

AF:

0.00294

Gnomad4 FIN exome

AF:

0.00857

Gnomad4 NFE exome

AF:

0.0162

Gnomad4 OTH exome

AF:

0.0113

GnomAD4 genome

AF:

0.00877

AC:

1335

AN:

152254

Hom.:

Cov.:

AF XY:

0.00806

AC XY:

600

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00265

Gnomad4 AMR

AF:

0.00458

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00136

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.00782

Gnomad4 NFE

AF:

0.0150

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.0115

Hom.:

Bravo

AF:

0.00776

TwinsUK

AF:

0.0148

AC:

ALSPAC

AF:

0.0171

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0142

AC:

122

ExAC

AF:

0.00785

AC:

953

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0123

EpiControl

AF:

0.0130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2018	This variant is associated with the following publications: (PMID: 27377421) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ADAMTS2: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Ehlers-Danlos syndrome, dermatosparaxis type

Benign:3

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	Natera, Inc.	Dec 09, 2019	- -
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

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 11, 2021

Variant summary: ADAMTS2 c.1993G>A (p.Gly665Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0078 in 251246 control chromosomes in the gnomAD database, including 21 homozygotes. The observed variant frequency is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in ADAMTS2 causing Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) phenotype (0.0029), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1993G>A in individuals affected with Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.097

FATHMM_MKL

Benign

0.56

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.5

D;.

REVEL

Benign

0.12

Sift

Benign

0.059

T;.

Sift4G

Benign

0.14

T;.

Polyphen

0.24

B;.

Vest4

0.33

MutPred

0.25

Gain of MoRF binding (P = 0.0138);Gain of MoRF binding (P = 0.0138);

MVP

0.37

MPC

0.50

ClinPred

0.060

GERP RS

4.5

Varity_R

0.24

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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