chr5-179129975-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014244.5(ADAMTS2):​c.2414C>G​(p.Thr805Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T805M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ADAMTS2
NM_014244.5 missense

Scores

10
8

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.39

Publications

8 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADAMTS2NM_014244.5 linkc.2414C>G p.Thr805Arg missense_variant Exon 16 of 22 ENST00000251582.12 NP_055059.2 O95450-1
ADAMTS2XM_047417895.1 linkc.1919C>G p.Thr640Arg missense_variant Exon 15 of 21 XP_047273851.1
ADAMTS2XM_047417896.1 linkc.1532C>G p.Thr511Arg missense_variant Exon 14 of 20 XP_047273852.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADAMTS2ENST00000251582.12 linkc.2414C>G p.Thr805Arg missense_variant Exon 16 of 22 1 NM_014244.5 ENSP00000251582.7 O95450-1
ADAMTS2ENST00000518335.3 linkc.2414C>G p.Thr805Arg missense_variant Exon 16 of 21 3 ENSP00000489888.2 A0A1B0GTY3
ADAMTS2ENST00000698889.1 linkn.2414C>G non_coding_transcript_exon_variant Exon 16 of 21 ENSP00000514008.1 A0A8V8TMU7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.0000119
AC:
3
AN:
251102
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461732
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727178
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000504
AC:
2
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53268
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1112008
Other (OTH)
AF:
0.00
AC:
0
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.550
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.26
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Benign
0.37
T;.
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.92
D
M_CAP
Benign
0.030
D
MetaRNN
Uncertain
0.47
T;T
MetaSVM
Benign
-0.86
T
MutationAssessor
Uncertain
2.1
M;.
PhyloP100
3.4
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-4.0
D;.
REVEL
Benign
0.29
Sift
Uncertain
0.013
D;.
Sift4G
Uncertain
0.027
D;.
Polyphen
1.0
D;.
Vest4
0.73
MutPred
0.57
Gain of phosphorylation at T808 (P = 0.0809);Gain of phosphorylation at T808 (P = 0.0809);
MVP
0.51
MPC
1.3
ClinPred
0.79
D
GERP RS
4.2
Varity_R
0.60
gMVP
0.87
Mutation Taster
=84/16
polymorphism

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

Other links and lift over

dbSNP: rs370350117; hg19: chr5-178556976; API