chrX-41344351-G-A

Variant names:

• chrX-41344351-G-A
• rs797045025
• NM_001356.5:c.977G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001356.5(DDX3X):​c.977G>A​(p.Arg326His) 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. R326C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: DDX3X NM_001356.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 9.94
• Publications: 14 publications found

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

ACMG classification

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

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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-41344350-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 521573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.966
• PP5: Variant X-41344351-G-A is Pathogenic according to our data. Variant chrX-41344351-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 208547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001356.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX3X	NM_001356.5	MANE Select	c.977G>A	p.Arg326His	missense	Exon 10 of 17	NP_001347.3
	DDX3X	NM_001193416.3		c.977G>A	p.Arg326His	missense	Exon 10 of 17	NP_001180345.1
	DDX3X	NM_001193417.3		c.929G>A	p.Arg310His	missense	Exon 9 of 16	NP_001180346.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX3X	ENST00000644876.2	MANE Select	c.977G>A	p.Arg326His	missense	Exon 10 of 17	ENSP00000494040.1
	DDX3X	ENST00000399959.7	TSL:1	c.974G>A	p.Arg325His	missense	Exon 10 of 17	ENSP00000382840.3
	DDX3X	ENST00000478993.5	TSL:1	n.977G>A		non_coding_transcript_exon	Exon 10 of 19	ENSP00000478443.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, X-linked 102 Pathogenic:4

Aug 06, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 32135084, , PS3_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000521573, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.614, 3CNET: 0.991, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26235985, PS2_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Jul 18, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is absent from gnomAD (v2, v3 and v4); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by multiple clinical laboratories (ClinVar). This variant has also been reported in the literature in multiple de novo individuals with DDX3X-related features (PMID: 26235985, 30125339, 32135084); This variant has been shown to be de novo in the proband by trio analysis (parental status confirmed). Additional information: Variant is predicted to result in a missense amino acid change from Arg to His; This variant is heterozygous; This gene is associated with X-linked dominant disease. Females may or may not be symptomatic (OMIM); Loss of function is a known mechanism of disease in this gene and is associated with Snijders Blok-type X-linked syndromic intellectual developmental disorder (MIM#300958).

Jul 13, 2018

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:2

Jun 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 18, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28135719, 26235985, 29346770, 30125339, 35982159, 36973392, 32135084, 33619735, 33057194)

Inborn genetic diseases Pathogenic:1

Oct 07, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Syndromic X-linked intellectual disability Claes-Jensen type Other:1

GenomeConnect - Brain Gene Registry

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 10-20-2017 by Lab GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.0018	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		9.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.90		Loss of methylation at R326 (P = 0.0323)
MVP		0.91
MPC		3.1
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.96
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs797045025; hg19: chrX-41203604; COSMIC: COSV101302329; COSMIC: COSV101302329;