rs966437723

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_014244.5(ADAMTS2):c.3088C>T(p.Arg1030*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ADAMTS2
NM_014244.5 stop_gained, splice_region

Scores

Splicing: ADA: 0.0009549

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -0.112

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Ehlers-Danlos syndrome, dermatosparaxis type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P, PanelApp Australia, Illumina

ADAMTS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 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 5-179122644-G-A is Pathogenic according to our data. Variant chr5-179122644-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 581454.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5 link	c.3088C>T	p.Arg1030*	stop_gained, splice_region_variant	Exon 20 of 22	ENST00000251582.12	NP_055059.2	O95450-1
ADAMTS2	XM_047417895.1 link	c.2593C>T	p.Arg865*	stop_gained, splice_region_variant	Exon 19 of 21		XP_047273851.1
ADAMTS2	XM_047417896.1 link	c.2206C>T	p.Arg736*	stop_gained, splice_region_variant	Exon 18 of 20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12 link	c.3088C>T	p.Arg1030*	stop_gained, splice_region_variant	Exon 20 of 22	1	NM_014244.5	ENSP00000251582.7		O95450-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

152642

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1398282

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

689706

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31684

American (AMR)

AF:

0.00

AC:

AN:

35786

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25164

East Asian (EAS)

AF:

0.00

AC:

AN:

35862

South Asian (SAS)

AF:

0.00

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48088

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5254

European-Non Finnish (NFE)

AF:

9.27e-7

AC:

AN:

1079268

Other (OTH)

AF:

0.0000173

AC:

AN:

57942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type

Pathogenic:1

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg1030*) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ADAMTS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 581454). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.26

Eigen_PC

Benign

-0.024

FATHMM_MKL

Benign

0.13

PhyloP100

-0.11

Vest4

0.78

GERP RS

0.55

Mutation Taster

=7/193

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00095

dbscSNV1_RF

Benign

0.39

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over