rs796052230

chrX-41346541-CAT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001356.5(DDX3X):c.1535_1536del(p.His512ArgfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: DDX3X NM_001356.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 9.27

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-41346541-CAT-C is Pathogenic according to our data. Variant chrX-41346541-CAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 207812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41346541-CAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDX3X	NM_001356.5	c.1535_1536del	p.His512ArgfsTer5	frameshift_variant	14/17	ENST00000644876.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDX3X	ENST00000644876.2	c.1535_1536del	p.His512ArgfsTer5	frameshift_variant	14/17		NM_001356.5	A1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Dec 27, 2022	PVS1, PM2, PP5 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 15, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	Recurrent variant, observed de novo in 3 female probands [Snijders Blok et al 2015] -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Apr 23, 2018	[ACMG/AMP: PVS1, PM1, PM2, PM6, PS4_Moderate] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], is de novo in origin as it was not detected in the submitted parental specimens (identity NOT confirmed) [PM6], has previously been observed in multiple unrelated patients with the same phenotype [PS4_Moderate]. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 12, 2022	Variant summary: DDX3X c.1535_1536delAT (p.His512ArgfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 181440 control chromosomes (gnomAD). c.1535_1536delAT has been reported in the literature in several heterozygous female individuals affected with X-Linked Intellectual Disability 102, including at least three cases where it was confirmed to be de novo (Snijders Blok_2015, Chanes_2019, Ziats_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2021	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31618753, 26235985, 28135719, 30817323, 32371413) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 09, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 207812). This premature translational stop signal has been observed in individual(s) with X-linked intellectual disability (PMID: 26235985). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His512Argfs*5) in the DDX3X gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DDX3X are known to be pathogenic (PMID: 26235985). -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2018

The c.1535_1536delAT pathogenic mutation, located in coding exon 14 of the DDX3X gene, results from a deletion of two nucleotides at nucleotide positions 1535 to 1536, causing a translational frameshift with a predicted alternate stop codon (p.H512Rfs*5). This alteration was detected as a de novo occurrence in two females with mild-to-moderate intellectual disability, hypotonia, ventricular enlargement, and precocious puberty (Snijders Blok L et al. Am. J. Hum. Genet., 2015 Aug;97:343-52). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Rare genetic intellectual disability Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

-

- -

X-linked intellectual disability-hypotonia-movement disorder syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Oct 04, 2022

PVS1;PM2_supporting;PM6;PP5 -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs796052230; hg19: chrX-41205794;