rs367796431

Variant names:

• chr5-179125113-C-T
• rs367796431
• NM_014244.5:c.2818G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_014244.5(ADAMTS2):​c.2818G>A​(p.Val940Met) variant causes a missense change. The variant allele was found at a frequency of 0.000207 in 1,612,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V940V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: ADAMTS2 NM_014244.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 5.96
• Publications: 1 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), G2P, Orphanet, Illumina, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.2818G>A	p.Val940Met	missense	Exon 19 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.2818G>A	p.Val940Met	missense	Exon 19 of 22	ENSP00000251582.7	O95450-1
	ADAMTS2	ENST00000957641.1		c.2761G>A	p.Val921Met	missense	Exon 19 of 22	ENSP00000627700.1
	ADAMTS2	ENST00000518335.3	TSL:3	c.2818G>A	p.Val940Met	missense	Exon 19 of 21	ENSP00000489888.2	A0A1B0GTY3

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000196 AC: 49 AN: 250364 AF XY: 0.000214

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000390

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000205 AC: 300 AN: 1460652 Hom.: 0 Cov.: 38 AF XY: 0.000216 AC XY: 157 AN XY: 726678

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86248

European-Finnish (FIN) AF: 0.0000382 AC: 2 AN: 52388

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000255 AC: 283 AN: 1111894

Other (OTH) AF: 0.000149 AC: 9 AN: 60362

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.000327 AC: 5 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000245 Hom.: 0

Bravo AF: 0.000170

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	Ehlers-Danlos syndrome, dermatosparaxis type (4)
-	3	-	not provided (3)
-	1	-	not specified (1)
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		6.0
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.017	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.52
MVP		0.64
MPC		1.0
ClinPred		0.53	D
GERP RS		4.6
Varity_R		0.12
gMVP		0.57
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs367796431; hg19: chr5-178552114;