X-41346342-C-G

Variant names:

• chrX-41346342-C-G
• rs1555954105
• NM_001356.5:c.1429C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_001356.5(DDX3X):​c.1429C>G​(p.Gln477Glu) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: DDX3X NM_001356.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.86

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 Likely_pathogenic. Variant got 8 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, 0.952
• PP5: Variant X-41346342-C-G is Pathogenic according to our data. Variant chrX-41346342-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 559627.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDX3X	NM_001356.5	c.1429C>G	p.Gln477Glu	missense_variant	Exon 13 of 17	ENST00000644876.2	NP_001347.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX3X	ENST00000644876.2	c.1429C>G	p.Gln477Glu	missense_variant	Exon 13 of 17		NM_001356.5	ENSP00000494040.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, X-linked 102 Pathogenic:1

Oct 06, 2017

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;D;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	.;.;D;D;D;D;D;D;D;D;D;D;D;.;.;D;.;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.6	M;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.8	.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	.;D;D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.93, 0.94, 0.92
MutPred		0.85		Gain of phosphorylation at S476 (P = 0.1041);Gain of phosphorylation at S476 (P = 0.1041);Gain of phosphorylation at S476 (P = 0.1041);Gain of phosphorylation at S476 (P = 0.1041);.;.;Gain of phosphorylation at S476 (P = 0.1041);.;Gain of phosphorylation at S476 (P = 0.1041);.;.;Gain of phosphorylation at S476 (P = 0.1041);.;.;.;.;.;.;.;
MVP		0.96
MPC		2.7
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.95

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

LitVar

Other links and lift over

dbSNP: rs1555954105; hg19: chrX-41205595;