rs1054480

chr5-179113974-G-A

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.3529C>T(p.Pro1177Ser) variant causes a missense change. The variant allele was found at a frequency of 0.291 in 1,613,916 control chromosomes in the GnomAD database, including 71,235 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1177L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.25 (5426 hom., cov: 32)
  • Exomes 𝑓: 0.30 (65809 hom.)
• Consequence: ADAMTS2 NM_014244.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.99

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=0.004896581).
• BP6: Variant 5-179113974-G-A is Benign according to our data. Variant chr5-179113974-G-A is described in ClinVar as [Benign]. Clinvar id is 353083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179113974-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS2	NM_014244.5	c.3529C>T	p.Pro1177Ser	missense_variant	22/22	ENST00000251582.12
ADAMTS2	XM_047417895.1	c.3034C>T	p.Pro1012Ser	missense_variant	21/21
ADAMTS2	XM_047417896.1	c.2647C>T	p.Pro883Ser	missense_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.3529C>T	p.Pro1177Ser	missense_variant	22/22	1	NM_014244.5	P2

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37273 AN: 151918 Hom.: 5425 Cov.: 32

Gnomad AFR AF: 0.0806

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.376

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.325

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.277

GnomAD3 exomes AF: 0.308 AC: 77472 AN: 251482 Hom.: 12671 AF XY: 0.312 AC XY: 42391 AN XY: 135918

Gnomad AFR exome AF: 0.0739

Gnomad AMR exome AF: 0.408

Gnomad ASJ exome AF: 0.312

Gnomad EAS exome AF: 0.319

Gnomad SAS exome AF: 0.371

Gnomad FIN exome AF: 0.292

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.311

GnomAD4 exome AF: 0.295 AC: 431642 AN: 1461880 Hom.: 65809 Cov.: 43 AF XY: 0.298 AC XY: 217028 AN XY: 727242

Gnomad4 AFR exome AF: 0.0723

Gnomad4 AMR exome AF: 0.403

Gnomad4 ASJ exome AF: 0.310

Gnomad4 EAS exome AF: 0.356

Gnomad4 SAS exome AF: 0.368

Gnomad4 FIN exome AF: 0.288

Gnomad4 NFE exome AF: 0.290

Gnomad4 OTH exome AF: 0.287

GnomAD4 genome AF: 0.245 AC: 37282 AN: 152036 Hom.: 5426 Cov.: 32 AF XY: 0.248 AC XY: 18432 AN XY: 74292

Gnomad4 AFR AF: 0.0807

Gnomad4 AMR AF: 0.353

Gnomad4 ASJ AF: 0.312

Gnomad4 EAS AF: 0.319

Gnomad4 SAS AF: 0.373

Gnomad4 FIN AF: 0.285

Gnomad4 NFE AF: 0.294

Gnomad4 OTH AF: 0.274

Alfa AF: 0.290 Hom.: 16260

Bravo AF: 0.243

TwinsUK AF: 0.297 AC: 1102

ALSPAC AF: 0.280 AC: 1081

ESP6500AA AF: 0.0810 AC: 357

ESP6500EA AF: 0.294 AC: 2527

ExAC AF: 0.300 AC: 36398

Asia WGS AF: 0.314 AC: 1093 AN: 3478

EpiCase AF: 0.305

EpiControl AF: 0.301

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Benign:6

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	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Feb 04, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.098
Eigen_PC	Benign	0.0069
FATHMM_MKL	Uncertain	0.91	D
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	0.78	P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.10
Sift	Benign	0.13	T
Sift4G	Benign	0.94	T
Polyphen		0.65	P
Vest4		0.053
MPC		0.41
ClinPred		0.030	T
GERP RS		5.0
Varity_R		0.075
gMVP		0.18

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: rs1054480; hg19: chr5-178540975; COSMIC: COSV52368813; COSMIC: COSV52368813;