rs59567206

Variant names:

• chr5-179207703-T-C
• rs59567206
• NM_014244.5:c.701A>G

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.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. 16/21 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
• Publications: 7 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=0.0020564795).
• BP6: Variant 5-179207703-T-C is Benign according to our data. Variant chr5-179207703-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 353138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0623 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014244.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	NM_014244.5	MANE Select	c.701A>G	p.Asp234Gly	missense	Exon 4 of 22	NP_055059.2
	ADAMTS2	NM_021599.4		c.701A>G	p.Asp234Gly	missense	Exon 4 of 11	NP_067610.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.701A>G	p.Asp234Gly	missense	Exon 4 of 22	ENSP00000251582.7
	ADAMTS2	ENST00000274609.5	TSL:1	c.701A>G	p.Asp234Gly	missense	Exon 4 of 11	ENSP00000274609.5
	ADAMTS2	ENST00000518335.3	TSL:3	c.701A>G	p.Asp234Gly	missense	Exon 4 of 21	ENSP00000489888.2

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

GnomAD2 exomes AF: 0.00778 AC: 1939 AN: 249290 AF XY: 0.00638

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 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

African (AFR) AF: 0.0681 AC: 2281 AN: 33474

American (AMR) AF: 0.00378 AC: 169 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000995 AC: 26 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00384 AC: 331 AN: 86256

European-Finnish (FIN) AF: 0.0109 AC: 555 AN: 50986

Middle Eastern (MID) AF: 0.00608 AC: 35 AN: 5760

European-Non Finnish (NFE) AF: 0.00332 AC: 3695 AN: 1111952

Other (OTH) AF: 0.00699 AC: 422 AN: 60376

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

African (AFR) AF: 0.0643 AC: 2672 AN: 41524

American (AMR) AF: 0.00653 AC: 100 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5168

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4822

European-Finnish (FIN) AF: 0.0105 AC: 112 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00307 AC: 209 AN: 68006

Other (OTH) AF: 0.0137 AC: 29 AN: 2116

Alfa AF: 0.00671 Hom.: 42

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Ehlers-Danlos syndrome, dermatosparaxis type (3)
-	-	2	not specified (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-0.40
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.043
Sift	Benign	0.46	T
Sift4G	Benign	0.51	T
Polyphen		0.0	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
Mutation Taster		=98/2	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: rs59567206; hg19: chr5-178634704;