NM_014244.5:c.733G>A

Variant names:

• chr5-179207671-C-T
• rs398829
• NM_014244.5:c.733G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.34 (9215 hom., cov: 33)
  • Exomes 𝑓: 0.31 (76386 hom.)
• Consequence: ADAMTS2 NM_014244.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.205
• Publications: 39 publications found

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 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, dermatosparaxis type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P, PanelApp Australia, Illumina

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 353134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.733G>A	p.Val245Ile	missense_variant	Exon 4 of 22	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4	c.733G>A	p.Val245Ile	missense_variant	Exon 4 of 11		NP_067610.1
ADAMTS2	XM_047417895.1	c.238G>A	p.Val80Ile	missense_variant	Exon 3 of 21		XP_047273851.1
ADAMTS2	XM_047417896.1	c.-150G>A		5_prime_UTR_variant	Exon 2 of 20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.733G>A	p.Val245Ile	missense_variant	Exon 4 of 22	1	NM_014244.5	ENSP00000251582.7
ADAMTS2	ENST00000274609.5	c.733G>A	p.Val245Ile	missense_variant	Exon 4 of 11	1		ENSP00000274609.5
ADAMTS2	ENST00000518335.3	c.733G>A	p.Val245Ile	missense_variant	Exon 4 of 21	3		ENSP00000489888.2
ADAMTS2	ENST00000698889.1	n.733G>A		non_coding_transcript_exon_variant	Exon 4 of 21			ENSP00000514008.1

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51278 AN: 151994 Hom.: 9208 Cov.: 33

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

GnomAD2 exomes AF: 0.350 AC: 87833 AN: 250832 AF XY: 0.358

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 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.: 64 AF XY: 0.320 AC XY: 232518 AN XY: 726844

African (AFR) AF: 0.389 AC: 13020 AN: 33480

American (AMR) AF: 0.252 AC: 11250 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 9159 AN: 26130

East Asian (EAS) AF: 0.648 AC: 25734 AN: 39700

South Asian (SAS) AF: 0.506 AC: 43677 AN: 86252

European-Finnish (FIN) AF: 0.303 AC: 15950 AN: 52584

Middle Eastern (MID) AF: 0.373 AC: 2154 AN: 5768

European-Non Finnish (NFE) AF: 0.284 AC: 316018 AN: 1111932

Other (OTH) AF: 0.336 AC: 20302 AN: 60384

GnomAD4 genome AF: 0.337 AC: 51330 AN: 152112 Hom.: 9215 Cov.: 33 AF XY: 0.343 AC XY: 25481 AN XY: 74374

African (AFR) AF: 0.386 AC: 15989 AN: 41470

American (AMR) AF: 0.284 AC: 4337 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1182 AN: 3472

East Asian (EAS) AF: 0.655 AC: 3383 AN: 5168

South Asian (SAS) AF: 0.510 AC: 2461 AN: 4826

European-Finnish (FIN) AF: 0.316 AC: 3351 AN: 10594

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.289 AC: 19635 AN: 67976

Other (OTH) AF: 0.332 AC: 700 AN: 2110

Alfa AF: 0.311 Hom.: 20062

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

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Benign:6

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2014

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Sep 29, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 25, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
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	N
MetaRNN	Benign	0.000011	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.2	L;.;L
PhyloP100		-0.20
PrimateAI	Benign	0.41	T
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	T
GERP RS		1.2
Varity_R		0.024
gMVP		0.26
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs398829; hg19: chr5-178634672; COSMIC: COSV51071879;