rs144138766

chr5-179125038-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_014244.5(ADAMTS2):c.2893G>A(p.Glu965Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000343 in 1,608,298 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (1 hom.)
• Consequence: ADAMTS2 NM_014244.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 7.68

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 Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011239171).
• BP6: Variant 5-179125038-C-T is Benign according to our data. Variant chr5-179125038-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 469674.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000357 (520/1456470) while in subpopulation AMR AF= 0.00508 (221/43484). AF 95% confidence interval is 0.00453. There are 1 homozygotes in gnomad4_exome. There are 214 alleles in male gnomad4_exome subpopulation. Median coverage is 38. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS2	NM_014244.5	c.2893G>A	p.Glu965Lys	missense_variant	19/22	ENST00000251582.12
ADAMTS2	XM_047417895.1	c.2398G>A	p.Glu800Lys	missense_variant	18/21
ADAMTS2	XM_047417896.1	c.2011G>A	p.Glu671Lys	missense_variant	17/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.2893G>A	p.Glu965Lys	missense_variant	19/22	1	NM_014244.5	P2
ADAMTS2	ENST00000518335.3	c.2893G>A	p.Glu965Lys	missense_variant	19/21	3		A2
ADAMTS2	ENST00000698889.1	c.2893G>A	p.Glu965Lys	missense_variant, NMD_transcript_variant	19/21

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 151710 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

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: 0.0000736

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000944 AC: 234 AN: 247778 Hom.: 1 AF XY: 0.000744 AC XY: 100 AN XY: 134494

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.00583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000215

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000357 AC: 520 AN: 1456470 Hom.: 1 Cov.: 38 AF XY: 0.000295 AC XY: 214 AN XY: 724628

Gnomad4 AFR exome AF: 0.000270

Gnomad4 AMR exome AF: 0.00508

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000510

Gnomad4 SAS exome AF: 0.0000701

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000247

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000204 AC: 31 AN: 151828 Hom.: 0 Cov.: 33 AF XY: 0.000162 AC XY: 12 AN XY: 74186

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000426 Hom.: 0

Bravo AF: 0.000555

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000817 AC: 99

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 25, 2022	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The c.2893G>A (p.E965K) alteration is located in exon 19 (coding exon 19) of the ADAMTS2 gene. This alteration results from a G to A substitution at nucleotide position 2893, causing the glutamic acid (E) at amino acid position 965 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

ADAMTS2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 18, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.3	D;.
REVEL	Uncertain	0.43
Sift	Benign	0.079	T;.
Sift4G	Uncertain	0.028	D;.
Polyphen		1.0	D;.
Vest4		0.89
MVP		0.63
MPC		1.3
ClinPred		0.073	T
GERP RS		5.3
Varity_R		0.33
gMVP		0.31

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: rs144138766; hg19: chr5-178552039; COSMIC: COSV52363790; COSMIC: COSV52363790;