rs150989902

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_014244.5(ADAMTS2):c.3551C>T(p.Pro1184Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000127 in 1,613,964 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 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

ADAMTS2
NM_014244.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 1.59

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 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=0.0080733).

BP6

Variant 5-179113952-G-A is Benign according to our data. Variant chr5-179113952-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 451540.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ADAMTS2	NM_014244.5 linkuse as main transcript	c.3551C>T	p.Pro1184Leu	missense_variant	22/22	ENST00000251582.12	NP_055059.2
ADAMTS2	XM_047417895.1 linkuse as main transcript	c.3056C>T	p.Pro1019Leu	missense_variant	21/21		XP_047273851.1
ADAMTS2	XM_047417896.1 linkuse as main transcript	c.2669C>T	p.Pro890Leu	missense_variant	20/20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12 linkuse as main transcript	c.3551C>T	p.Pro1184Leu	missense_variant	22/22	1	NM_014244.5	ENSP00000251582	P2	O95450-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00606

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000235

AC:

AN:

251494

Hom.:

AF XY:

0.000213

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00427

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000125

AC:

183

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00440

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.000145

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00606

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000286

Hom.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000222

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 01, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 13, 2019

Variant summary: ADAMTS2 c.3551C>T (p.Pro1184Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 251494 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ADAMTS2 causing Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) (0.00023 vs 0.0029), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3551C>T in individuals affected with Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) and no experimental evidence demonstrating its impact on protein function have been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 16, 2020

Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.060

FATHMM_MKL

Benign

0.68

M_CAP

Benign

0.023

MetaRNN

Benign

0.0081

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.0

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.7

REVEL

Benign

0.032

Sift

Benign

0.042

Sift4G

Benign

0.37

Polyphen

0.49

Vest4

0.24

MVP

0.48

MPC

0.42

ClinPred

0.034

GERP RS

4.1

Varity_R

0.073

gMVP

0.24

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

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