Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_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).
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]
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the DDX3X gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 93 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Gene score misZ: 4.3295 (above the threshold of 3.09). GenCC associations: The gene is linked to 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: {Likely_pathogenic=1, Uncertain_significance=1}.
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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
Nov 14, 2016
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
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);.;.;.;.;.;.;.;