5-179207671-C-T

Position:

chr5-179207671-C-T

Variant summary

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

The NM_014244.5(ADAMTS2):c.733G>A(p.Val245Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 1,613,066 control chromosomes in the GnomAD database, including 85,601 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 9215 hom., cov: 33)

Exomes 𝑓: 0.31 ( 76386 hom. )

Consequence

ADAMTS2
NM_014244.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.205

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=1.0532214E-5).

BP6

Variant 5-179207671-C-T is Benign according to our data. Variant chr5-179207671-C-T is described in ClinVar as [Benign]. Clinvar id is 353134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179207671-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.636 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.733G>A	p.Val245Ile	missense_variant	4/22	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4 linkuse as main transcript	c.733G>A	p.Val245Ile	missense_variant	4/11		NP_067610.1
ADAMTS2	XM_047417895.1 linkuse as main transcript	c.238G>A	p.Val80Ile	missense_variant	3/21		XP_047273851.1
ADAMTS2	XM_047417896.1 linkuse as main transcript	c.-150G>A		5_prime_UTR_variant	2/20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12 linkuse as main transcript	c.733G>A	p.Val245Ile	missense_variant	4/22	1	NM_014244.5	ENSP00000251582	P2	O95450-1
ADAMTS2	ENST00000274609.5 linkuse as main transcript	c.733G>A	p.Val245Ile	missense_variant	4/11	1		ENSP00000274609		O95450-2
ADAMTS2	ENST00000518335.3 linkuse as main transcript	c.733G>A	p.Val245Ile	missense_variant	4/21	3		ENSP00000489888	A2
ADAMTS2	ENST00000698889.1 linkuse as main transcript	c.733G>A	p.Val245Ile	missense_variant, NMD_transcript_variant	4/21			ENSP00000514008

Frequencies

GnomAD3 genomes

AF:

0.337

AC:

51278

AN:

151994

Hom.:

9208

Cov.:

show subpopulations

Gnomad AFR

AF:

0.385

Gnomad AMI

AF:

0.205

Gnomad AMR

AF:

0.284

Gnomad ASJ

AF:

0.340

Gnomad EAS

AF:

0.654

Gnomad SAS

AF:

0.510

Gnomad FIN

AF:

0.316

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.289

Gnomad OTH

AF:

0.335

GnomAD3 exomes

AF:

0.350

AC:

87833

AN:

250832

Hom.:

17178

AF XY:

0.358

AC XY:

48583

AN XY:

135730

show subpopulations

Gnomad AFR exome

AF:

0.391

Gnomad AMR exome

AF:

0.246

Gnomad ASJ exome

AF:

0.346

Gnomad EAS exome

AF:

0.659

Gnomad SAS exome

AF:

0.508

Gnomad FIN exome

AF:

0.308

Gnomad NFE exome

AF:

0.293

Gnomad OTH exome

AF:

0.333

GnomAD4 exome

AF:

0.313

AC:

457264

AN:

1460954

Hom.:

76386

Cov.:

AF XY:

0.320

AC XY:

232518

AN XY:

726844

show subpopulations

Gnomad4 AFR exome

AF:

0.389

Gnomad4 AMR exome

AF:

0.252

Gnomad4 ASJ exome

AF:

0.351

Gnomad4 EAS exome

AF:

0.648

Gnomad4 SAS exome

AF:

0.506

Gnomad4 FIN exome

AF:

0.303

Gnomad4 NFE exome

AF:

0.284

Gnomad4 OTH exome

AF:

0.336

GnomAD4 genome

AF:

0.337

AC:

51330

AN:

152112

Hom.:

9215

Cov.:

AF XY:

0.343

AC XY:

25481

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.386

Gnomad4 AMR

AF:

0.284

Gnomad4 ASJ

AF:

0.340

Gnomad4 EAS

AF:

0.655

Gnomad4 SAS

AF:

0.510

Gnomad4 FIN

AF:

0.316

Gnomad4 NFE

AF:

0.289

Gnomad4 OTH

AF:

0.332

Alfa

AF:

0.310

Hom.:

15142

Bravo

AF:

0.333

TwinsUK

AF:

0.259

AC:

959

ALSPAC

AF:

0.278

AC:

1073

ESP6500AA

AF:

0.380

AC:

1674

ESP6500EA

AF:

0.297

AC:

2555

ExAC

AF:

0.354

AC:

43030

Asia WGS

AF:

0.530

AC:

1838

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type

Benign:6

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

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 29, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Nov 25, 2016

Variant summary: The ADAMTS2 c.733G>A (p.Val245Ile) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a benign outcome for this variant . This variant was found in 42957/120864 control chromosomes (8516 homozygotes) at a frequency of 0.355416, which is approximately 123 times the estimated maximal expected allele frequency of a pathogenic ADAMTS2 variant (0.0028868), suggesting this variant is likely a benign polymorphism. . The variant of interest has been cited as Polymorphism in published report(s). Taking together, based on the prevalence in general population the variant was classified as Benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

5.2

DANN

Benign

0.90

DEOGEN2

Benign

0.13

T;.;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.093

MetaRNN

Benign

0.000011

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.2

L;.;L

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.41

PROVEAN

Benign

0.070

N;.;N

REVEL

Benign

0.039

Sift

Benign

0.48

T;.;T

Sift4G

Benign

0.46

T;.;T

Polyphen

0.0020

B;.;B

Vest4

0.031

MPC

0.33

ClinPred

0.0012

GERP RS

1.2

Varity_R

0.024

gMVP

0.26

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