chrX-41334292-C-G

Variant names:

• chrX-41334292-C-G
• NM_001356.5:c.40C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001356.5(DDX3X):​c.40C>G​(p.Gln14Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000912 in 1,096,972 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: DDX3X NM_001356.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.62

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3380673).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDX3X	NM_001356.5	c.40C>G	p.Gln14Glu	missense_variant	Exon 1 of 17	ENST00000644876.2	NP_001347.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX3X	ENST00000644876.2	c.40C>G	p.Gln14Glu	missense_variant	Exon 1 of 17		NM_001356.5	ENSP00000494040.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096972 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 362378

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T;T;.;T;.;.;.;.;.;.;.;.;.
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	.;.;D;D;D;.;T;D;D;D;D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M;M;.;.;M;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.3	.;.;.;.;N;.;N;.;.;.;.;N;.
REVEL	Benign	0.13
Sift	Uncertain	0.023	.;.;.;.;D;.;.;.;.;.;.;T;.
Sift4G	Benign	0.079	.;T;T;T;T;.;T;.;.;.;.;T;.
Polyphen		0.063	B;B;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.52, 0.51, 0.50, 0.52, 0.88, 0.44
MutPred		0.47		Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);
MVP		0.73
MPC		1.6
ClinPred		0.77	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-41193545;