X-41345505-ATCAG-AT

Variant names:

• chrX-41345506-TCAG-T
• NM_001356.5:c.1274_1276delCAG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PM4_Supporting

The NM_001356.5(DDX3X):​c.1274_1276delCAG​(p.Ser425_Asp426delinsTyr) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 22)
• Consequence: DDX3X NM_001356.5 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.87
• 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]

RN7SL15P (HGNC:46031): (RNA, 7SL, cytoplasmic 15, pseudogene)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001356.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001356.5. Strenght limited to Supporting due to length of the change: 1aa.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX3X	NM_001356.5	MANE Select	c.1274_1276delCAG	p.Ser425_Asp426delinsTyr	disruptive_inframe_deletion	Exon 12 of 17	NP_001347.3
	DDX3X	NM_001193416.3		c.1274_1276delCAG	p.Ser425_Asp426delinsTyr	disruptive_inframe_deletion	Exon 12 of 17	NP_001180345.1	A0A2R8YFS5
	DDX3X	NM_001193417.3		c.1226_1228delCAG	p.Ser409_Asp410delinsTyr	disruptive_inframe_deletion	Exon 11 of 16	NP_001180346.1	O00571-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX3X	ENST00000644876.2	MANE Select	c.1274_1276delCAG	p.Ser425_Asp426delinsTyr	disruptive_inframe_deletion	Exon 12 of 17	ENSP00000494040.1	O00571-1
	DDX3X	ENST00000399959.7	TSL:1	c.1271_1273delCAG	p.Ser424_Asp425delinsTyr	disruptive_inframe_deletion	Exon 12 of 17	ENSP00000382840.3	A0A2U3TZJ9
	DDX3X	ENST00000478993.5	TSL:1	n.1274_1276delCAG		non_coding_transcript_exon	Exon 12 of 19	ENSP00000478443.1	O00571-1

Frequencies

GnomAD3 genomes Cov.: 22

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

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-41204759;