4-72283389-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_014243.3(ADAMTS3):​c.3365G>A​(p.Ser1122Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000882 in 1,613,748 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.00057 ( 2 hom., cov: 32)
Exomes 𝑓: 0.00091 ( 13 hom. )

Consequence

ADAMTS3
NM_014243.3 missense

Scores

18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.854
Variant links:
Genes affected
ADAMTS3 (HGNC:219): (ADAM metallopeptidase with thrombospondin type 1 motif 3) 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 protease. This protease, a member of the procollagen aminopropeptidase subfamily of proteins, may play a role in the processing of type II fibrillar collagen in articular cartilage. [provided by RefSeq, Feb 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0050585866).
BP6
Variant 4-72283389-C-T is Benign according to our data. Variant chr4-72283389-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2654804.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
BS2
High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADAMTS3NM_014243.3 linkc.3365G>A p.Ser1122Asn missense_variant Exon 22 of 22 ENST00000286657.10 NP_055058.2 O15072Q96AY5B7Z2U9
ADAMTS3XM_011532421.2 linkc.3308G>A p.Ser1103Asn missense_variant Exon 22 of 22 XP_011530723.1
ADAMTS3XM_011532422.4 linkc.3281G>A p.Ser1094Asn missense_variant Exon 22 of 22 XP_011530724.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADAMTS3ENST00000286657.10 linkc.3365G>A p.Ser1122Asn missense_variant Exon 22 of 22 1 NM_014243.3 ENSP00000286657.4 O15072

Frequencies

GnomAD3 genomes
AF:
0.000579
AC:
88
AN:
152110
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00260
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00809
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000515
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00169
AC:
423
AN:
250912
Hom.:
7
AF XY:
0.00223
AC XY:
303
AN XY:
135576
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.00268
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0108
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000450
Gnomad OTH exome
AF:
0.00131
GnomAD4 exome
AF:
0.000914
AC:
1336
AN:
1461520
Hom.:
13
Cov.:
31
AF XY:
0.00125
AC XY:
910
AN XY:
727010
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.00283
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0104
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000246
Gnomad4 OTH exome
AF:
0.00109
GnomAD4 genome
AF:
0.000572
AC:
87
AN:
152228
Hom.:
2
Cov.:
32
AF XY:
0.000672
AC XY:
50
AN XY:
74414
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00260
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00789
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000515
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000584
Hom.:
0
Bravo
AF:
0.000438
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.00182
AC:
221
Asia WGS
AF:
0.00346
AC:
12
AN:
3478
EpiCase
AF:
0.000709
EpiControl
AF:
0.000949

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Aug 14, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3365G>A (p.S1122N) alteration is located in exon 22 (coding exon 22) of the ADAMTS3 gene. This alteration results from a G to A substitution at nucleotide position 3365, causing the serine (S) at amino acid position 1122 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

ADAMTS3-related disorder Benign:1
Oct 01, 2023
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1
Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ADAMTS3: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Benign
-0.59
T
BayesDel_noAF
Benign
-0.62
CADD
Benign
11
DANN
Benign
0.77
DEOGEN2
Benign
0.012
T;T
Eigen
Benign
-0.70
Eigen_PC
Benign
-0.61
FATHMM_MKL
Benign
0.44
N
LIST_S2
Benign
0.47
.;T
MetaRNN
Benign
0.0051
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.97
L;L
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-0.63
N;.
REVEL
Benign
0.078
Sift
Benign
0.23
T;.
Sift4G
Benign
0.45
T;T
Polyphen
0.0
B;B
Vest4
0.046
MVP
0.58
MPC
0.11
ClinPred
0.0096
T
GERP RS
3.5
Varity_R
0.041
gMVP
0.25

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.

Other links and lift over

dbSNP: rs148581726; hg19: chr4-73149106; API