rs1057519430

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.86

Publications

23 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

intellectual disability, X-linked 102
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
X-linked syndromic intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen, Illumina
Toriello-Carey syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
X-linked intellectual disability-hypotonia-movement disorder syndrome
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

DDX3X links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. 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). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, X-linked 102, X-linked syndromic intellectual disability, Toriello-Carey syndrome, X-linked intellectual disability-hypotonia-movement disorder syndrome.

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 VariationId is 375367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDX3X	NM_001356.5 link	c.1703C>T	p.Pro568Leu	missense_variant	Exon 15 of 17	ENST00000644876.2	NP_001347.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX3X	ENST00000644876.2 link	c.1703C>T	p.Pro568Leu	missense_variant	Exon 15 of 17		NM_001356.5	ENSP00000494040.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Mar 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 08, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. This variant is not present in population databases (ExAC no frequency). 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). Experimental studies have shown that this variant affects DDX3X protein function (PMID: 32135084). For these reasons, this variant has been classified as Pathogenic. -

Intellectual disability, X-linked 102

Pathogenic:2

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

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. -

Apr 13, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Jul 28, 2017

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

EBV-positive nodal T- and NK-cell lymphoma

Pathogenic:1

Department of Clinical Pathology, School of Medicine, Fujita Health University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;D;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

.;.;D;D;D;D;D;D;D;D;D;D;D;.;.;D;.;D;D

M_CAP

Uncertain

0.20

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

MutationAssessor

Pathogenic

3.8

H;H;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

7.9

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-9.5

.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Pathogenic

0.0

.;D;D;D;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

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.99

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over