rs137853146

Positions:

chr5-179272926-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_014244.5(ADAMTS2):c.673C>T(p.Gln225Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000783 in 1,610,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

ADAMTS2
NM_014244.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 2.66

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-179272926-G-A is Pathogenic according to our data. Variant chr5-179272926-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ADAMTS2	NM_014244.5 linkuse as main transcript	c.673C>T	p.Gln225Ter	stop_gained	3/22	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4 linkuse as main transcript	c.673C>T	p.Gln225Ter	stop_gained	3/11		NP_067610.1
ADAMTS2	XM_047417895.1 linkuse as main transcript	c.178C>T	p.Gln60Ter	stop_gained	2/21		XP_047273851.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12 linkuse as main transcript	c.673C>T	p.Gln225Ter	stop_gained	3/22	1	NM_014244.5	ENSP00000251582	P2	O95450-1
ADAMTS2	ENST00000274609.5 linkuse as main transcript	c.673C>T	p.Gln225Ter	stop_gained	3/11	1		ENSP00000274609		O95450-2
ADAMTS2	ENST00000518335.3 linkuse as main transcript	c.673C>T	p.Gln225Ter	stop_gained	3/21	3		ENSP00000489888	A2
ADAMTS2	ENST00000698889.1 linkuse as main transcript	c.673C>T	p.Gln225Ter	stop_gained, NMD_transcript_variant	3/21			ENSP00000514008

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000149

AC:

AN:

247994

Hom.:

AF XY:

0.000149

AC XY:

AN XY:

134418

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00299

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.000493

GnomAD4 exome

AF:

0.0000809

AC:

118

AN:

1457876

Hom.:

Cov.:

AF XY:

0.0000827

AC XY:

AN XY:

725324

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00341

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000359

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 26, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 03, 2020	NM_014244.4(ADAMTS2):c.673C>T(Q225) is classified as pathogenic in the context of type VIIC Ehlers-Danlos syndrome. Sources cited for classification include the following: PMID 10417273. Classification of NM_014244.4(ADAMTS2):c.673C>T(Q225) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 04, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 31, 2018	The ADAMTS2 c.673C>T (p.Gln225Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The variant has been reported in a homozygous state in a total of six individuals with Ehlers-Danlos syndrome (Colige et al. 1999; Bar-Yosef et al. 2008). One of the newborn individuals exhibited multiple non-traumatic congenital skull fractures and multiple other defects related to a connective tissue abnormality (Bar-Yosef et al. 2008). Control data are unavailable for the p.Gln225Ter variant, which is reported at a frequency of 0.003053 in the Ashkenazi Jewish population of the Genome Aggregation Database. Due to the potential impact of stop-gained variants and the available evidence, the p.Gln225Ter variant is classified as pathogenic for Ehlers-Danlos syndrome, dermatosparaxis type. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change creates a premature translational stop signal (p.Gln225*) in the ADAMTS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADAMTS2 are known to be pathogenic (PMID: 10417273). This variant is present in population databases (rs137853146, gnomAD 0.3%). This premature translational stop signal has been observed in individuals with Ehlers-Danlos syndrome, type VIIC (PMID: 10417273, 18973246). ClinVar contains an entry for this variant (Variation ID: 5502). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 24, 2021

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar as pathogenic (ClinVar Variant ID# 5502; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 10417273, 27175728, 26879370, 18973246, 26582918) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Benign

0.74

MutationTaster

Benign

1.0

A;A

Vest4

0.85

GERP RS

3.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over