rs1555951993
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_001356.5(DDX3X):c.113A>G(p.Tyr38Cys) 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 22)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
DDX3X
NM_001356.5 missense
NM_001356.5 missense
Scores
7
4
1
Clinical Significance
Conservation
PhyloP100: 8.12
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 Pathogenic. Variant got 15 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001356.5
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, DDX3X
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.881
PP5
?
Variant X-41339045-A-G is Pathogenic according to our data. Variant chrX-41339045-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 545446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DDX3X | NM_001356.5 | c.113A>G | p.Tyr38Cys | missense_variant | 3/17 | ENST00000644876.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DDX3X | ENST00000644876.2 | c.113A>G | p.Tyr38Cys | missense_variant | 3/17 | NM_001356.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 951166Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0AN XY: 282968
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
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0
AN:
951166
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Cov.:
17
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0
AN XY:
282968
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Intellectual disability, X-linked 102 Pathogenic:3
Pathogenic, criteria provided, single submitter | research | Laboratory of Human Genetics, Universidade de São Paulo | Mar 16, 2022 | Variant disclosed in a girl with intellectual disability and X-chromosome inactivation skewing. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Apr 19, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Apr 07, 2021 | This DDX3X variant (rs1555951993) is absent in a large population dataset and has an entry in ClinVar. Two bioinformatics tools queried predict that p.Tyr38Cys would be damaging, while another predicts it would be tolerated. The tyrosine residue at this position is strongly conserved across the vertebrate species assessed. This variant is not predicted to affect normal exon 3 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.113A>G to be likely pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 13, 2022 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 38 of the DDX3X protein (p.Tyr38Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of an X-linked intellectual disability syndrome (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 545446). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
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
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
Polyphen
D;D;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.74, 0.71, 0.74, 0.98
MutPred
Loss of phosphorylation at Y38 (P = 0.0384);Loss of phosphorylation at Y38 (P = 0.0384);Loss of phosphorylation at Y38 (P = 0.0384);Loss of phosphorylation at Y38 (P = 0.0384);Loss of phosphorylation at Y38 (P = 0.0384);Loss of phosphorylation at Y38 (P = 0.0384);.;Loss of phosphorylation at Y38 (P = 0.0384);.;.;Loss of phosphorylation at Y38 (P = 0.0384);.;.;
MVP
0.93
MPC
2.4
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
DS_AG_spliceai
Position offset: -6
Find out detailed SpliceAI scores and Pangolin per-transcript scores at