rs59567206

Positions:

• chr5-179207703-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014244.5(ADAMTS2):​c.701A>G​(p.Asp234Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00662 in 1,611,586 control chromosomes in the GnomAD database, including 201 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D234N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.021 (101 hom., cov: 33)
  • Exomes 𝑓: 0.0051 (100 hom.)
• Consequence: ADAMTS2 NM_014244.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.402

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020564795).
• BP6: Variant 5-179207703-T-C is Benign according to our data. Variant chr5-179207703-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 353138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179207703-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS2	NM_014244.5	c.701A>G	p.Asp234Gly	missense_variant	4/22	ENST00000251582.12
ADAMTS2	NM_021599.4	c.701A>G	p.Asp234Gly	missense_variant	4/11
ADAMTS2	XM_047417895.1	c.206A>G	p.Asp69Gly	missense_variant	3/21
ADAMTS2	XM_047417896.1	c.-182A>G		5_prime_UTR_variant	2/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.701A>G	p.Asp234Gly	missense_variant	4/22	1	NM_014244.5	P2
ADAMTS2	ENST00000274609.5	c.701A>G	p.Asp234Gly	missense_variant	4/11	1
ADAMTS2	ENST00000518335.3	c.701A>G	p.Asp234Gly	missense_variant	4/21	3		A2
ADAMTS2	ENST00000698889.1	c.701A>G	p.Asp234Gly	missense_variant, NMD_transcript_variant	4/21

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3130 AN: 152122 Hom.: 100 Cov.: 33

Gnomad AFR AF: 0.0641

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00307

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.00778 AC: 1939 AN: 249290 Hom.: 42 AF XY: 0.00638 AC XY: 862 AN XY: 135092

Gnomad AFR exome AF: 0.0639

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00382

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.00339

Gnomad OTH exome AF: 0.00704

GnomAD4 exome AF: 0.00515 AC: 7515 AN: 1459346 Hom.: 100 Cov.: 36 AF XY: 0.00498 AC XY: 3616 AN XY: 726108

Gnomad4 AFR exome AF: 0.0681

Gnomad4 AMR exome AF: 0.00378

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00384

Gnomad4 FIN exome AF: 0.0109

Gnomad4 NFE exome AF: 0.00332

Gnomad4 OTH exome AF: 0.00699

GnomAD4 genome AF: 0.0207 AC: 3146 AN: 152240 Hom.: 101 Cov.: 33 AF XY: 0.0199 AC XY: 1481 AN XY: 74432

Gnomad4 AFR AF: 0.0643

Gnomad4 AMR AF: 0.00653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0105

Gnomad4 NFE AF: 0.00307

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00570 Hom.: 26

Bravo AF: 0.0223

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.0701 AC: 309

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00912 AC: 1107

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00279

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

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	- -
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.	Sep 16, 2020	- -

not specified Benign:2

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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 13, 2021	- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 17, 2020

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.11
DANN	Benign	0.34
DEOGEN2	Benign	0.14	T;.;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0081	N
MetaRNN	Benign	0.0021	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.1	N;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.10	N;.;N
REVEL	Benign	0.043
Sift	Benign	0.46	T;.;T
Sift4G	Benign	0.51	T;.;T
Polyphen		0.0	B;.;B
Vest4		0.072
MVP		0.18
MPC		0.53
ClinPred		0.0016	T
GERP RS		-4.3
Varity_R		0.033
gMVP		0.57

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

Other links and lift over

dbSNP: rs59567206; hg19: chr5-178634704;