chrX-41345280-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R376H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 22)

Consequence

DDX3X
NM_001356.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 4.97

Publications

13 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001356.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-41345281-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 872857.Status of the report is no_assertion_criteria_provided, 0 stars.

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, 0.957

PP5

Variant X-41345280-C-T is Pathogenic according to our data. Variant chrX-41345280-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 207813.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.1126C>T	p.Arg376Cys	missense_variant	Exon 11 of 17	ENST00000644876.2	NP_001347.3	O00571-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX3X	ENST00000644876.2 link	c.1126C>T	p.Arg376Cys	missense_variant	Exon 11 of 17		NM_001356.5	ENSP00000494040.1		O00571-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Nov 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects DDX3X function (PMID: 26235985). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 207813). 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. This variant is not present in population databases (gnomAD no frequency). 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). -

Intellectual disability, X-linked 102

Pathogenic:4Other:1

Feb 18, 2019

Dobyns Lab, Seattle Children's Research Institute

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Recurrent variant, observed de novo in 3 female probands [Snijders Blok et al 2015] -

Aug 23, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS3 supporting, PS4 moderate, PM2 moderate, PM6 strong -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 06, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Congenital cerebellar hypoplasia

Pathogenic:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.37

T;T;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.99

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

M_CAP

Uncertain

0.14

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

MutationAssessor

Uncertain

2.6

M;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

5.0

PrimateAI

Pathogenic

0.81

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

GERP RS

5.4

PromoterAI

-0.035

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.98

Mutation Taster

=2/98

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