Genetic Variant ADAMTS2:p.Arg628Leu (chr5-179137837-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_014244.5(ADAMTS2):c.1883G>T(p.Arg628Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,420,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R628H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

ADAMTS2
NM_014244.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.827

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3373073).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014244.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	NM_014244.5	MANE Select	c.1883G>T	p.Arg628Leu	missense	Exon 12 of 22	NP_055059.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.1883G>T	p.Arg628Leu	missense	Exon 12 of 22	ENSP00000251582.7
ADAMTS2	ENST00000518335.3	TSL:3	c.1883G>T	p.Arg628Leu	missense	Exon 12 of 21	ENSP00000489888.2
ADAMTS2	ENST00000698889.1		n.1883G>T		non_coding_transcript_exon	Exon 12 of 21	ENSP00000514008.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.04e-7

AC:

AN:

1420252

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

702908

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32398

American (AMR)

AF:

0.00

AC:

AN:

39552

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25386

East Asian (EAS)

AF:

0.00

AC:

AN:

37022

South Asian (SAS)

AF:

0.00

AC:

AN:

80506

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48640

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5410

European-Non Finnish (NFE)

AF:

9.15e-7

AC:

AN:

1092510

Other (OTH)

AF:

0.00

AC:

AN:

58828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.047

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

Eigen

Benign

-0.033

Eigen_PC

Benign

0.023

FATHMM_MKL

Benign

0.55

M_CAP

Benign

0.032

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.1

PhyloP100

0.83

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.23

Sift

Benign

0.15

Sift4G

Benign

0.20

Polyphen

0.65

Vest4

0.58

MutPred

0.57

Loss of disorder (P = 0.0461)

MVP

0.59

MPC

0.83

ClinPred

0.84

GERP RS

4.7

Varity_R

0.12

gMVP

0.61

Mutation Taster

=91/9

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over