NM_001356.5:c.1486G>A
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3PP5_Moderate
The NM_001356.5(DDX3X):c.1486G>A(p.Val496Met) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V496G) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 23)
Consequence
DDX3X
NM_001356.5 missense
NM_001356.5 missense
Scores
12
3
2
Clinical Significance
Conservation
PhyloP100: 9.94
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 10 ACMG points.
PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_001356.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-41346400-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1706539.Status of the report is criteria_provided_single_submitter, 1 stars.
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, 0.83
PP5
Variant X-41346399-G-A is Pathogenic according to our data. Variant chrX-41346399-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 548024.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-41346399-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Intellectual disability, X-linked 102 Pathogenic:2Other:1
-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only
Observed in affected males w/de novo occurrence [Wang et al 2018, Nicola et al 2019] -
Jan 29, 2018
Mayo Clinic Laboratories, Mayo Clinic
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
May 07, 2020
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
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
Pathogenic
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
Pathogenic
H;H;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL
Uncertain
Sift
Pathogenic
.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Pathogenic
.;D;D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen
D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.88, 0.88, 0.78
MutPred
Gain of catalytic residue at V496 (P = 0.0702);Gain of catalytic residue at V496 (P = 0.0702);Gain of catalytic residue at V496 (P = 0.0702);Gain of catalytic residue at V496 (P = 0.0702);.;.;Gain of catalytic residue at V496 (P = 0.0702);.;Gain of catalytic residue at V496 (P = 0.0702);.;.;Gain of catalytic residue at V496 (P = 0.0702);.;.;.;.;.;.;.;
MVP
0.96
MPC
2.7
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