X-41344238-G-T

Variant names:

• chrX-41344238-G-T
• rs1255183431
• NM_001356.5:c.865-1G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001356.5(DDX3X):​c.865-1G>T variant causes a splice acceptor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: DDX3X NM_001356.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• 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 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.7, offset of 17, new splice context is: tatttttcataccgatctAGagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

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.865-1G>T		splice_acceptor intron	N/A	NP_001347.3
	DDX3X	NM_001193416.3		c.865-1G>T		splice_acceptor intron	N/A	NP_001180345.1
	DDX3X	NM_001193417.3		c.817-1G>T		splice_acceptor intron	N/A	NP_001180346.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX3X	ENST00000644876.2	MANE Select	c.865-1G>T		splice_acceptor intron	N/A	ENSP00000494040.1
	DDX3X	ENST00000399959.7	TSL:1	c.862-1G>T		splice_acceptor intron	N/A	ENSP00000382840.3
	DDX3X	ENST00000478993.5	TSL:1	n.865-1G>T		splice_acceptor intron	N/A	ENSP00000478443.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00 AC: 0 AN: 178756 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1094440 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 360748

African (AFR) AF: 0.00 AC: 0 AN: 26152

American (AMR) AF: 0.00 AC: 0 AN: 34303

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19243

East Asian (EAS) AF: 0.00 AC: 0 AN: 30181

South Asian (SAS) AF: 0.00 AC: 0 AN: 53237

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40507

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4106

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840800

Other (OTH) AF: 0.00 AC: 0 AN: 45911

GnomAD4 genome Cov.: 23

Alfa AF: 0.000668 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	34
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		9.9
GERP RS		4.6
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.76		Position offset: 18
DS_AL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1255183431; hg19: chrX-41203491;