rs1057523822
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5
The NM_001356.5(DDX3X):c.1226G>A(p.Gly409Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 22)
Consequence
DDX3X
NM_001356.5 missense
NM_001356.5 missense
Scores
11
4
2
Clinical Significance
Conservation
PhyloP100: 9.93
Genes affected
DDX3X (HGNC:2745): (DEAD-box helicase 3 X-linked) The protein encoded by this gene is a member of the large DEAD-box protein family, that is defined by the presence of the conserved Asp-Glu-Ala-Asp (DEAD) motif, and has ATP-dependent RNA helicase activity. This protein has been reported to display a high level of RNA-independent ATPase activity, and unlike most DEAD-box helicases, the ATPase activity is thought to be stimulated by both RNA and DNA. This protein has multiple conserved domains and is thought to play roles in both the nucleus and cytoplasm. Nuclear roles include transcriptional regulation, mRNP assembly, pre-mRNA splicing, and mRNA export. In the cytoplasm, this protein is thought to be involved in translation, cellular signaling, and viral replication. Misregulation of this gene has been implicated in tumorigenesis. This gene has a paralog located in the nonrecombining region of the Y chromosome. Pseudogenes sharing similarity to both this gene and the DDX3Y paralog are found on chromosome 4 and the X chromosome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
In a region_of_interest Interaction with HCV core protein (size 253) in uniprot entity DDX3X_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001356.5
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DDX3X. . Gene score misZ 4.3295 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked intellectual disability-hypotonia-movement disorder syndrome, Toriello-Carey syndrome, intellectual disability, X-linked 102, X-linked syndromic intellectual disability.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.862
PP5
Variant X-41345459-G-A is Pathogenic according to our data. Variant chrX-41345459-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 390568.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DDX3X | NM_001356.5 | c.1226G>A | p.Gly409Asp | missense_variant | 12/17 | ENST00000644876.2 | NP_001347.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DDX3X | ENST00000644876.2 | c.1226G>A | p.Gly409Asp | missense_variant | 12/17 | NM_001356.5 | ENSP00000494040.1 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD3 genomes
Cov.:
22
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome Cov.: 22
GnomAD4 genome
Cov.:
22
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 09, 2016 | The G409D variant in the DDX3X gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G409D variant is not observed in large population cohorts (Lek et al., 2016; Exome Variant Server). The G409D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The G409D variant is a strong candidate for a pathogenic variant - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 14, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;.;D;D;D;D;D;D;D;D;D;D;D;.;.;D;.;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL
Pathogenic
Sift
Pathogenic
.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Pathogenic
.;D;D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen
D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.84, 0.84, 0.84, 0.81
MutPred
Gain of catalytic residue at G409 (P = 0.044);Gain of catalytic residue at G409 (P = 0.044);Gain of catalytic residue at G409 (P = 0.044);Gain of catalytic residue at G409 (P = 0.044);.;.;Gain of catalytic residue at G409 (P = 0.044);.;Gain of catalytic residue at G409 (P = 0.044);.;.;Gain of catalytic residue at G409 (P = 0.044);.;.;.;.;.;.;.;
MVP
0.94
MPC
3.1
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at