rs117222015

Positions:

• chr5-179207640-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014244.5(ADAMTS2):​c.764G>A​(p.Arg255Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,613,770 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R255R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00085 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (13 hom.)
• Consequence: ADAMTS2 NM_014244.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.601

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038357973).
• BP6: Variant 5-179207640-C-T is Benign according to our data. Variant chr5-179207640-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 353132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179207640-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000853 (130/152342) while in subpopulation EAS AF= 0.0081 (42/5184). AF 95% confidence interval is 0.00616. There are 1 homozygotes in gnomad4. There are 70 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS2	NM_014244.5	c.764G>A	p.Arg255Gln	missense_variant	4/22	ENST00000251582.12
ADAMTS2	NM_021599.4	c.764G>A	p.Arg255Gln	missense_variant	4/11
ADAMTS2	XM_047417895.1	c.269G>A	p.Arg90Gln	missense_variant	3/21
ADAMTS2	XM_047417896.1	c.-119G>A		5_prime_UTR_variant	2/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.764G>A	p.Arg255Gln	missense_variant	4/22	1	NM_014244.5	P2
ADAMTS2	ENST00000274609.5	c.764G>A	p.Arg255Gln	missense_variant	4/11	1
ADAMTS2	ENST00000518335.3	c.764G>A	p.Arg255Gln	missense_variant	4/21	3		A2
ADAMTS2	ENST00000698889.1	c.764G>A	p.Arg255Gln	missense_variant, NMD_transcript_variant	4/21

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 130 AN: 152224 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00808

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.000658

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00202 AC: 508 AN: 251320 Hom.: 5 AF XY: 0.00218 AC XY: 296 AN XY: 135906

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00936

Gnomad SAS exome AF: 0.00797

Gnomad FIN exome AF: 0.000694

Gnomad NFE exome AF: 0.000422

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00111 AC: 1625 AN: 1461428 Hom.: 13 Cov.: 62 AF XY: 0.00128 AC XY: 927 AN XY: 727028

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0101

Gnomad4 SAS exome AF: 0.00738

Gnomad4 FIN exome AF: 0.000604

Gnomad4 NFE exome AF: 0.000415

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.000853 AC: 130 AN: 152342 Hom.: 1 Cov.: 34 AF XY: 0.000940 AC XY: 70 AN XY: 74496

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00810

Gnomad4 SAS AF: 0.00808

Gnomad4 FIN AF: 0.000658

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000721 Hom.: 0

Bravo AF: 0.000676

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00226 AC: 274

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 21, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ADAMTS2: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2020	- -

ADAMTS2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2019

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

Ehlers-Danlos syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 17, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.9
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.087	N
MetaRNN	Benign	0.0038	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.98	N;.;N
REVEL	Benign	0.025
Sift	Benign	0.12	T;.;T
Sift4G	Benign	0.063	T;.;T
Polyphen		0.0010	B;.;B
Vest4		0.094
MVP		0.32
MPC		0.47
ClinPred		0.011	T
GERP RS		3.5
Varity_R		0.028
gMVP		0.33

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: rs117222015; hg19: chr5-178634641; COSMIC: COSV51081062;