NM_014244.5:c.3529C>T

Variant names:

• chr5-179113974-G-A
• rs1054480
• NM_014244.5:c.3529C>T

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.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. 13/21 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
• Publications: 43 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: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Illumina, Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 353083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.359 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	NM_014244.5	MANE Select	c.3529C>T	p.Pro1177Ser	missense	Exon 22 of 22	NP_055059.2	O95450-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.3529C>T	p.Pro1177Ser	missense	Exon 22 of 22	ENSP00000251582.7	O95450-1
	ADAMTS2	ENST00000957641.1		c.3472C>T	p.Pro1158Ser	missense	Exon 22 of 22	ENSP00000627700.1
	ADAMTS2	ENST00000522937.1	TSL:2	n.*90C>T		downstream_gene	N/A

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

GnomAD2 exomes AF: 0.308 AC: 77472 AN: 251482 AF XY: 0.312

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 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

African (AFR) AF: 0.0723 AC: 2420 AN: 33480

American (AMR) AF: 0.403 AC: 18039 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 8112 AN: 26136

East Asian (EAS) AF: 0.356 AC: 14139 AN: 39700

South Asian (SAS) AF: 0.368 AC: 31745 AN: 86258

European-Finnish (FIN) AF: 0.288 AC: 15404 AN: 53420

Middle Eastern (MID) AF: 0.314 AC: 1810 AN: 5768

European-Non Finnish (NFE) AF: 0.290 AC: 322663 AN: 1111998

Other (OTH) AF: 0.287 AC: 17310 AN: 60396

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

African (AFR) AF: 0.0807 AC: 3349 AN: 41510

American (AMR) AF: 0.353 AC: 5392 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 1084 AN: 3470

East Asian (EAS) AF: 0.319 AC: 1639 AN: 5140

South Asian (SAS) AF: 0.373 AC: 1799 AN: 4818

European-Finnish (FIN) AF: 0.285 AC: 3007 AN: 10568

Middle Eastern (MID) AF: 0.342 AC: 100 AN: 292

European-Non Finnish (NFE) AF: 0.294 AC: 19942 AN: 67944

Other (OTH) AF: 0.274 AC: 576 AN: 2104

Alfa AF: 0.282 Hom.: 21816

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Ehlers-Danlos syndrome, dermatosparaxis type (6)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.0
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
Mutation Taster		=94/6	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: rs1054480; hg19: chr5-178540975; COSMIC: COSV52368813; COSMIC: COSV52368813;