Genetic Variant NM_014244.5:c.3014C>A (chr5-179122718-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014244.5(ADAMTS2):c.3014C>A(p.Ala1005Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 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. A1005T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ADAMTS2
NM_014244.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.149

Publications

7 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.048223525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5 link	c.3014C>A	p.Ala1005Glu	missense_variant	Exon 20 of 22	ENST00000251582.12	NP_055059.2	O95450-1
ADAMTS2	XM_047417895.1 link	c.2519C>A	p.Ala840Glu	missense_variant	Exon 19 of 21		XP_047273851.1
ADAMTS2	XM_047417896.1 link	c.2132C>A	p.Ala711Glu	missense_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.3014C>A	p.Ala1005Glu	missense_variant	Exon 20 of 22	1	NM_014244.5	ENSP00000251582.7		O95450-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

157232

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1400052

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690698

African (AFR)

AF:

0.00

AC:

AN:

31702

American (AMR)

AF:

0.00

AC:

AN:

35862

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25170

East Asian (EAS)

AF:

0.00

AC:

AN:

35850

South Asian (SAS)

AF:

0.00

AC:

AN:

79336

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1080036

Other (OTH)

AF:

0.00

AC:

AN:

58086

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

2.7

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.092

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.048

M_CAP

Benign

0.0062

MetaRNN

Benign

0.048

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.030

N;.

PhyloP100

-0.15

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.83

N;.

REVEL

Benign

0.14

Sift

Benign

0.49

T;.

Sift4G

Benign

0.88

T;.

Polyphen

0.17

B;.

Vest4

0.29

MutPred

0.53

Gain of loop (P = 0.1081);Gain of loop (P = 0.1081);

MVP

0.35

MPC

0.60

ClinPred

0.10

GERP RS

-1.5

Varity_R

0.064

gMVP

0.25

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over