16-89957637-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001242818.2(DEF8):c.349C>T(p.Arg117Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,567,756 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 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
DEF8
NM_001242818.2 missense
NM_001242818.2 missense
Scores
12
2
1
Clinical Significance
Conservation
PhyloP100: 7.21
Genes affected
DEF8 (HGNC:25969): (differentially expressed in FDCP 8 homolog) Predicted to enable metal ion binding activity. Predicted to be involved in lysosome localization; positive regulation of bone resorption; and positive regulation of ruffle assembly. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.822
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DEF8 | NM_001242818.2 | c.349C>T | p.Arg117Trp | missense_variant | 5/13 | ENST00000563594.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DEF8 | ENST00000563594.6 | c.349C>T | p.Arg117Trp | missense_variant | 5/13 | 1 | NM_001242818.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152242Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000113 AC: 2AN: 177564Hom.: 0 AF XY: 0.0000211 AC XY: 2AN XY: 94910
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GnomAD4 exome AF: 0.0000155 AC: 22AN: 1415514Hom.: 0 Cov.: 31 AF XY: 0.0000186 AC XY: 13AN XY: 700284
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152242Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74378
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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 | Jul 26, 2022 | The c.532C>T (p.R178W) alteration is located in exon 5 (coding exon 4) of the DEF8 gene. This alteration results from a C to T substitution at nucleotide position 532, causing the arginine (R) at amino acid position 178 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;.;.;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift
Pathogenic
D;D;.;.;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
D;.;D;D;.;.;.;.;D;.;D;.;D;.;.;D;.
Vest4
MutPred
0.51
.;.;.;.;.;.;.;.;Loss of disorder (P = 5e-04);.;.;.;.;.;.;.;.;
MVP
MPC
0.77
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at