X-41346607-C-CG

Variant names:

• chrX-41346607-C-CG
• rs1555954287
• NM_001356.5:c.1601dupG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001356.5(DDX3X):​c.1601dupG​(p.Val535CysfsTer12) 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 (★). Synonymous variant affecting the same amino acid position (i.e. R534R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: DDX3X NM_001356.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.94
• Publications: 0 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 12 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-41346607-C-CG is Pathogenic according to our data. Variant chrX-41346607-C-CG is described in ClinVar as Pathogenic. ClinVar VariationId is 521145.Status of the report is criteria_provided_single_submitter, 1 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.1601dupG	p.Val535CysfsTer12	frameshift	Exon 14 of 17	NP_001347.3
	DDX3X	NM_001193416.3		c.1601dupG	p.Val535CysfsTer12	frameshift	Exon 14 of 17	NP_001180345.1
	DDX3X	NM_001193417.3		c.1553dupG	p.Val519CysfsTer12	frameshift	Exon 13 of 16	NP_001180346.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX3X	ENST00000644876.2	MANE Select	c.1601dupG	p.Val535CysfsTer12	frameshift	Exon 14 of 17	ENSP00000494040.1
	DDX3X	ENST00000399959.7	TSL:1	c.1598dupG	p.Val534CysfsTer12	frameshift	Exon 14 of 17	ENSP00000382840.3
	DDX3X	ENST00000478993.5	TSL:1	n.1601dupG		non_coding_transcript_exon	Exon 14 of 19	ENSP00000478443.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Jun 15, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9
Mutation Taster		=0/200	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: rs1555954287; hg19: chrX-41205860;