rs1555951993

Variant names:

• chrX-41339045-A-G
• rs1555951993
• NM_001356.5:c.113A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001363819.1(DDX3X):​c.-446A>G variant causes a 5 prime UTR premature start codon gain 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: DDX3X NM_001363819.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.12
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: Illumina, ClinGen
• 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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881
• PP5: Variant X-41339045-A-G is Pathogenic according to our data. Variant chrX-41339045-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 545446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363819.1. 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.113A>G	p.Tyr38Cys	missense	Exon 3 of 17	NP_001347.3
	DDX3X	NM_001363819.1		c.-446A>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 17	NP_001350748.1	A0A2R8YDT5
	DDX3X	NM_001193416.3		c.113A>G	p.Tyr38Cys	missense	Exon 3 of 17	NP_001180345.1	A0A2R8YFS5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX3X	ENST00000644876.2	MANE Select	c.113A>G	p.Tyr38Cys	missense	Exon 3 of 17	ENSP00000494040.1	O00571-1
	DDX3X	ENST00000399959.7	TSL:1	c.110A>G	p.Tyr37Cys	missense	Exon 3 of 17	ENSP00000382840.3	A0A2U3TZJ9
	DDX3X	ENST00000478993.5	TSL:1	n.113A>G		non_coding_transcript_exon	Exon 3 of 19	ENSP00000478443.1	O00571-1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 951166 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 282968

African (AFR) AF: 0.00 AC: 0 AN: 21286

American (AMR) AF: 0.00 AC: 0 AN: 23788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16171

East Asian (EAS) AF: 0.00 AC: 0 AN: 25335

South Asian (SAS) AF: 0.00 AC: 0 AN: 35661

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3025

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 750829

Other (OTH) AF: 0.00 AC: 0 AN: 39273

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Intellectual disability, X-linked 102 (3)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.6	D
REVEL	Uncertain	0.63
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.74
MutPred		0.56		Loss of phosphorylation at Y38 (P = 0.0384)
MVP		0.93
MPC		2.4
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.72
gMVP		0.81
Mutation Taster		=36/64	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -6

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

Other links and lift over

dbSNP: rs1555951993; hg19: chrX-41198298; COSMIC: COSV67864387; COSMIC: COSV67864387;