chr12-43369297-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_025003.5(ADAMTS20):​c.5531G>A​(p.Cys1844Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000331 in 1,512,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

ADAMTS20
NM_025003.5 missense

Scores

8
7
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.96
Variant links:
Genes affected
ADAMTS20 (HGNC:17178): (ADAM metallopeptidase with thrombospondin type 1 motif 20) The protein encoded by this gene is a member of the ADAMTS family of zinc-dependent proteases. The encoded protein has a signal peptide that is cleaved to release the mature peptide, which is secreted and found in the extracellular matrix. This protein may be involved in tissue remodeling. [provided by RefSeq, Sep 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADAMTS20NM_025003.5 linkc.5531G>A p.Cys1844Tyr missense_variant Exon 37 of 39 ENST00000389420.8 NP_079279.3
ADAMTS20XM_011538754.3 linkc.5534G>A p.Cys1845Tyr missense_variant Exon 37 of 39 XP_011537056.1
ADAMTS20XM_017019979.2 linkc.4319G>A p.Cys1440Tyr missense_variant Exon 30 of 32 XP_016875468.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADAMTS20ENST00000389420.8 linkc.5531G>A p.Cys1844Tyr missense_variant Exon 37 of 39 1 NM_025003.5 ENSP00000374071.3 P59510-3

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151952
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
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:
0.000480
GnomAD3 exomes
AF:
0.0000113
AC:
2
AN:
176562
Hom.:
0
AF XY:
0.0000105
AC XY:
1
AN XY:
95684
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000102
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000294
AC:
4
AN:
1360864
Hom.:
0
Cov.:
28
AF XY:
0.00000297
AC XY:
2
AN XY:
673866
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000134
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151952
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74224
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000480
Bravo
AF:
0.0000189

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 30, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.5531G>A (p.C1844Y) alteration is located in exon 37 (coding exon 37) of the ADAMTS20 gene. This alteration results from a G to A substitution at nucleotide position 5531, causing the cysteine (C) at amino acid position 1844 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.054
T
BayesDel_noAF
Benign
-0.16
CADD
Pathogenic
27
DANN
Uncertain
1.0
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.66
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Uncertain
0.094
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Uncertain
-0.28
T
MutationAssessor
Pathogenic
3.1
M
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-8.7
D
REVEL
Uncertain
0.47
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Vest4
0.86
MutPred
0.89
Gain of catalytic residue at R1843 (P = 0.0207);
MVP
0.70
MPC
0.31
ClinPred
1.0
D
GERP RS
4.2
gMVP
0.91

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: rs937887527; hg19: chr12-43763100; API