chr5-179139982-G-T

Position:

• chr5-179139982-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014244.5(ADAMTS2):​c.1683C>A​(p.Asp561Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ADAMTS2 NM_014244.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.622

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.1683C>A	p.Asp561Glu	missense_variant	11/22	ENST00000251582.12	NP_055059.2
ADAMTS2	XM_047417895.1	c.1188C>A	p.Asp396Glu	missense_variant	10/21		XP_047273851.1
ADAMTS2	XM_047417896.1	c.801C>A	p.Asp267Glu	missense_variant	9/20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.1683C>A	p.Asp561Glu	missense_variant	11/22	1	NM_014244.5	ENSP00000251582.7
ADAMTS2	ENST00000518335.3	c.1683C>A	p.Asp561Glu	missense_variant	11/21	3		ENSP00000489888.2
ADAMTS2	ENST00000698889.1	n.1683C>A		non_coding_transcript_exon_variant	11/21			ENSP00000514008.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461784 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 26, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 30, 2021	This sequence change replaces aspartic acid with glutamic acid at codon 561 of the ADAMTS2 protein (p.Asp561Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with ADAMTS2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	8.9
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.23	N
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Uncertain	-0.087	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.0060	D;.
Sift4G	Uncertain	0.0030	D;.
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.54		Gain of methylation at K559 (P = 0.1304);Gain of methylation at K559 (P = 0.1304);
MVP		0.83
MPC		1.2
ClinPred		0.99	D
GERP RS		-7.0
Varity_R		0.32
gMVP		0.73

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: rs368700721; hg19: chr5-178566983;