rs398829

Variant names:

• chr5-179207671-C-T
• rs398829
• NM_014244.5:c.733G>A
• ADAMTS2 p.Val245Ile

Your query was ambiguous. Multiple possible variants found:

• chr5-179207671-C-T
• chr5-179207671-C-A
• chr5-179207671-C-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.733G>A​(p.Val245Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 1,613,066 control chromosomes in the GnomAD database, including 85,601 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.34 (9215 hom., cov: 33)
  • Exomes 𝑓: 0.31 (76386 hom.)
• Consequence: ADAMTS2 NM_014244.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.205
• Publications: 39 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: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Illumina

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0532214E-5).
• BP6: Variant 5-179207671-C-T is Benign according to our data. Variant chr5-179207671-C-T is described in ClinVar as Benign. ClinVar VariationId is 353134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.636 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.733G>A	p.Val245Ile	missense	Exon 4 of 22	NP_055059.2	O95450-1
	ADAMTS2	NM_021599.4		c.733G>A	p.Val245Ile	missense	Exon 4 of 11	NP_067610.1	O95450-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.733G>A	p.Val245Ile	missense	Exon 4 of 22	ENSP00000251582.7	O95450-1
	ADAMTS2	ENST00000274609.5	TSL:1	c.733G>A	p.Val245Ile	missense	Exon 4 of 11	ENSP00000274609.5	O95450-2
	ADAMTS2	ENST00000957641.1		c.733G>A	p.Val245Ile	missense	Exon 4 of 22	ENSP00000627700.1

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51278 AN: 151994 Hom.: 9208 Cov.: 33

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.654

Gnomad SAS AF: 0.510

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.335

GnomAD2 exomes AF: 0.350 AC: 87833 AN: 250832 AF XY: 0.358

Gnomad AFR exome AF: 0.391

Gnomad AMR exome AF: 0.246

Gnomad ASJ exome AF: 0.346

Gnomad EAS exome AF: 0.659

Gnomad FIN exome AF: 0.308

Gnomad NFE exome AF: 0.293

Gnomad OTH exome AF: 0.333

GnomAD4 exome AF: 0.313 AC: 457264 AN: 1460954 Hom.: 76386 Cov.: 64 AF XY: 0.320 AC XY: 232518 AN XY: 726844

African (AFR) AF: 0.389 AC: 13020 AN: 33480

American (AMR) AF: 0.252 AC: 11250 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 9159 AN: 26130

East Asian (EAS) AF: 0.648 AC: 25734 AN: 39700

South Asian (SAS) AF: 0.506 AC: 43677 AN: 86252

European-Finnish (FIN) AF: 0.303 AC: 15950 AN: 52584

Middle Eastern (MID) AF: 0.373 AC: 2154 AN: 5768

European-Non Finnish (NFE) AF: 0.284 AC: 316018 AN: 1111932

Other (OTH) AF: 0.336 AC: 20302 AN: 60384

GnomAD4 genome AF: 0.337 AC: 51330 AN: 152112 Hom.: 9215 Cov.: 33 AF XY: 0.343 AC XY: 25481 AN XY: 74374

African (AFR) AF: 0.386 AC: 15989 AN: 41470

American (AMR) AF: 0.284 AC: 4337 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1182 AN: 3472

East Asian (EAS) AF: 0.655 AC: 3383 AN: 5168

South Asian (SAS) AF: 0.510 AC: 2461 AN: 4826

European-Finnish (FIN) AF: 0.316 AC: 3351 AN: 10594

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.289 AC: 19635 AN: 67976

Other (OTH) AF: 0.332 AC: 700 AN: 2110

Alfa AF: 0.311 Hom.: 20062

Bravo AF: 0.333

Asia WGS AF: 0.530 AC: 1838 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Ehlers-Danlos syndrome, dermatosparaxis type (6)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.2
DANN	Benign	0.90
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.093	N
MetaRNN	Benign	0.000011	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.20
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.039
Sift	Benign	0.48	T
Sift4G	Benign	0.46	T
Varity_R		0.024
gMVP		0.26
Mutation Taster		=99/1	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs398829;

hg19: chr5-178634672;

COSMIC: COSV51071879;