rs796052231

Positions:

• chrX-41345280-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001356.5(DDX3X):​c.1126C>T​(p.Arg376Cys) variant causes a missense change. 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)
• Consequence: DDX3X NM_001356.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 4.97

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]

DDX3X (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DDX3X. . Gene score misZ 4.3295 (greater than the threshold 3.09). GenCC has associacion of gene with 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, 0.957
• PP5: Variant X-41345280-C-T is Pathogenic according to our data. Variant chrX-41345280-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 207813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41345280-C-T is described in Lovd as [Pathogenic]. Variant chrX-41345280-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDX3X	NM_001356.5	c.1126C>T	p.Arg376Cys	missense_variant	11/17	ENST00000644876.2	NP_001347.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX3X	ENST00000644876.2	c.1126C>T	p.Arg376Cys	missense_variant	11/17		NM_001356.5	ENSP00000494040.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 22, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 376 of the DDX3X protein (p.Arg376Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with DDX3X-related conditions (PMID: 26235985, 28135719). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207813). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects DDX3X function (PMID: 26235985). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Intellectual disability, X-linked 102 Pathogenic:4 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 23, 2021	ACMG classification criteria: PS3 supporting, PS4 moderate, PM2 moderate, PM6 strong -
not provided, no classification provided	literature only	GeneReviews	-	Recurrent variant, observed de novo in 3 female probands [Snijders Blok et al 2015] -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 06, 2015	- -
Pathogenic, no assertion criteria provided	research	Dobyns Lab, Seattle Children's Research Institute	Feb 18, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The DDX3X c.1126C>T (p.Arg376Cys) variant has been reported in heterozygous state in multiple individuals affected with Mental Retardation, X-Linked 102 (Snijders Blok et al). The p.Arg376Cys variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It has been submitted to ClinVar with varying interpretation as Pathogenic and Likely pathogenic. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid Arg at position 376 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Congenital cerebellar hypoplasia Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T;T;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	.;.;D;D;D;D;D;D;D;D;D;D;D;.;.;D;.;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.9	.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;D;D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.67, 0.69, 0.67, 0.64
MutPred		0.88		Loss of disorder (P = 0.0245);Loss of disorder (P = 0.0245);Loss of disorder (P = 0.0245);Loss of disorder (P = 0.0245);.;.;Loss of disorder (P = 0.0245);.;Loss of disorder (P = 0.0245);.;.;Loss of disorder (P = 0.0245);.;.;.;.;.;.;.;
MVP		0.95
MPC		3.2
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.98

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: rs796052231; hg19: chrX-41204533; COSMIC: COSV67863865; COSMIC: COSV67863865;