5-179273003-G-T

Variant names:

• chr5-179273003-G-T
• rs76704342
• NM_014244.5:c.596C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014244.5(ADAMTS2):​c.596C>A​(p.Ala199Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A199S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ADAMTS2 NM_014244.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.147
• Publications: 5 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0872744).

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.596C>A	p.Ala199Glu	missense	Exon 3 of 22	NP_055059.2	O95450-1
	ADAMTS2	NM_021599.4		c.596C>A	p.Ala199Glu	missense	Exon 3 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.596C>A	p.Ala199Glu	missense	Exon 3 of 22	ENSP00000251582.7	O95450-1
	ADAMTS2	ENST00000274609.5	TSL:1	c.596C>A	p.Ala199Glu	missense	Exon 3 of 11	ENSP00000274609.5	O95450-2
	ADAMTS2	ENST00000957641.1		c.596C>A	p.Ala199Glu	missense	Exon 3 of 22	ENSP00000627700.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251050 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461094 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 726882

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52634

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Ehlers-Danlos syndrome, dermatosparaxis type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	3.4
DANN	Benign	0.64
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.024	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L
PhyloP100		0.15
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.050
Sift	Benign	0.68	T
Sift4G	Benign	0.91	T
Polyphen		0.042	B
Vest4		0.27
MutPred		0.67		Gain of disorder (P = 0.0448)
MVP		0.35
MPC		0.48
ClinPred		0.034	T
GERP RS		1.2
Varity_R		0.055
gMVP		0.54
Mutation Taster		=98/2	polymorphism

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: rs76704342; hg19: chr5-178700004;