chr12-43376330-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.5126G>A(p.Cys1709Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000543 in 1,545,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000032 ( 0 hom. )
Consequence
ADAMTS20
NM_025003.5 missense, splice_region
NM_025003.5 missense, splice_region
Scores
13
2
2
Splicing: ADA: 0.9997
2
Clinical Significance
Conservation
PhyloP100: 6.46
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]
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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, 0.971
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADAMTS20 | NM_025003.5 | c.5126G>A | p.Cys1709Tyr | missense_variant, splice_region_variant | 34/39 | ENST00000389420.8 | |
ADAMTS20 | XM_011538754.3 | c.5129G>A | p.Cys1710Tyr | missense_variant, splice_region_variant | 34/39 | ||
ADAMTS20 | XM_017019979.2 | c.3914G>A | p.Cys1305Tyr | missense_variant, splice_region_variant | 27/32 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADAMTS20 | ENST00000389420.8 | c.5126G>A | p.Cys1709Tyr | missense_variant, splice_region_variant | 34/39 | 1 | NM_025003.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000256 AC: 39AN: 152152Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000765 AC: 12AN: 156818Hom.: 0 AF XY: 0.0000607 AC XY: 5AN XY: 82384
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GnomAD4 exome AF: 0.0000323 AC: 45AN: 1393726Hom.: 0 Cov.: 30 AF XY: 0.0000276 AC XY: 19AN XY: 687668
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GnomAD4 genome ? AF: 0.000256 AC: 39AN: 152152Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16AN XY: 74338
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 24, 2023 | The c.5126G>A (p.C1709Y) alteration is located in exon 34 (coding exon 34) of the ADAMTS20 gene. This alteration results from a G to A substitution at nucleotide position 5126, causing the cysteine (C) at amino acid position 1709 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at