rs140022033

Positions:

• chr5-179125136-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_014244.5(ADAMTS2):​c.2795G>A​(p.Arg932Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,612,998 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: ADAMTS2 NM_014244.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 2.57

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013914257).
• BP6: Variant 5-179125136-C-T is Benign according to our data. Variant chr5-179125136-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 377440.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr5-179125136-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.2795G>A	p.Arg932Gln	missense_variant	19/22	ENST00000251582.12	NP_055059.2
ADAMTS2	XM_047417895.1	c.2300G>A	p.Arg767Gln	missense_variant	18/21		XP_047273851.1
ADAMTS2	XM_047417896.1	c.1913G>A	p.Arg638Gln	missense_variant	17/20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.2795G>A	p.Arg932Gln	missense_variant	19/22	1	NM_014244.5	ENSP00000251582	P2
ADAMTS2	ENST00000518335.3	c.2795G>A	p.Arg932Gln	missense_variant	19/21	3		ENSP00000489888	A2
ADAMTS2	ENST00000698889.1	c.2795G>A	p.Arg932Gln	missense_variant, NMD_transcript_variant	19/21			ENSP00000514008

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00175

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00113 AC: 284 AN: 250274 Hom.: 0 AF XY: 0.00107 AC XY: 145 AN XY: 135466

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00265

Gnomad NFE exome AF: 0.00182

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00123 AC: 1795 AN: 1460660 Hom.: 1 Cov.: 37 AF XY: 0.00125 AC XY: 911 AN XY: 726680

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00283

Gnomad4 NFE exome AF: 0.00142

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000967 AC XY: 72 AN XY: 74486

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.00175

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.000922

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00127 AC: 154

EpiCase AF: 0.00136

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ADAMTS2: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2021	- -

Ehlers-Danlos syndrome, dermatosparaxis type Uncertain:1 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Ehlers-Danlos syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.63	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	0.83	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.39	N;.
REVEL	Benign	0.13
Sift	Benign	0.12	T;.
Sift4G	Benign	0.14	T;.
Polyphen		0.93	P;.
Vest4		0.41
MVP		0.50
MPC		0.48
ClinPred		0.021	T
GERP RS		4.4
Varity_R		0.054
gMVP		0.070

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140022033; hg19: chr5-178552137;