rs1057519430

chrX-41346946-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001356.5(DDX3X):c.1703C>T(p.Pro568Leu) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P568S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: DDX3X NM_001356.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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 Pathogenic. Variant got 15 ACMG points.

• PM1: In a domain Helicase C-terminal (size 161) in uniprot entity DDX3X_HUMAN there are 58 pathogenic changes around while only 1 benign (98%) 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, 0.869
• PP5: Variant X-41346946-C-T is Pathogenic according to our data. Variant chrX-41346946-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 375367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41346946-C-T is described in Lovd as [Pathogenic]. Variant chrX-41346946-C-T is described in Lovd as [Likely_pathogenic]. Variant chrX-41346946-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDX3X	NM_001356.5	c.1703C>T	p.Pro568Leu	missense_variant	15/17	ENST00000644876.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDX3X	ENST00000644876.2	c.1703C>T	p.Pro568Leu	missense_variant	15/17		NM_001356.5	A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 08, 2021	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects DDX3X protein function (PMID: 32135084). This variant has been observed in individual(s) with clinical features of DDX3X-related intellectual disability syndrome (PMID: 28371085, 26235985, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 375367). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 568 of the DDX3X protein (p.Pro568Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2017	- -

Intellectual disability, X-linked 102 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 13, 2023	- -
Pathogenic, no assertion criteria provided	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	This variant was identified, de novo, in an individual with developmental delay, intellectual disability, microcephaly, cortical visual impairment, delayed myelination on brain imaging, short stature and hypotonia. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;D;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.8	H;H;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
Polyphen		1.0	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.86, 0.90, 0.87, 0.81
MutPred		0.57		Gain of catalytic residue at P568 (P = 0.0037);Gain of catalytic residue at P568 (P = 0.0037);Gain of catalytic residue at P568 (P = 0.0037);Gain of catalytic residue at P568 (P = 0.0037);.;.;Gain of catalytic residue at P568 (P = 0.0037);.;Gain of catalytic residue at P568 (P = 0.0037);.;.;Gain of catalytic residue at P568 (P = 0.0037);.;.;.;.;.;.;.;
MVP		0.89
MPC		2.7
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.99

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: rs1057519430; hg19: chrX-41206199; COSMIC: COSV67863241; COSMIC: COSV67863241;