rs12008523

Variant names:

• chrX-41333436-C-T
• rs12008523
• ENST00000478993.5:n.-817C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000478993.5(DDX3X):​n.-817C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., 109 hem., cov: 20)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: DDX3X ENST00000478993.5 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0270
• 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

ENSG00000301689 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant X-41333436-C-T is Benign according to our data. Variant chrX-41333436-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1194345.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00502 (542/107952) while in subpopulation AFR AF = 0.017 (502/29588). AF 95% confidence interval is 0.0157. There are 4 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 XL,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000478993.5. 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	NR_126093.1		n.129C>T		non_coding_transcript_exon	Exon 1 of 19

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX3X	ENST00000478993.5	TSL:1	n.-817C>T		non_coding_transcript_exon	Exon 1 of 19	ENSP00000478443.1	O00571-1
	DDX3X	ENST00000478993.5	TSL:1	n.-817C>T		5_prime_UTR	Exon 1 of 19	ENSP00000478443.1	O00571-1
	DDX3X	ENST00000625837.2	TSL:5	c.-817C>T		5_prime_UTR	Exon 1 of 19	ENSP00000486306.1	A0A0D9SF53

Frequencies

GnomAD3 genomes AF: 0.00503 AC: 543 AN: 107908 Hom.: 4 Cov.: 20

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000193

Gnomad OTH AF: 0.00486

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 610 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 216

African (AFR) AF: 0.00 AC: 0 AN: 6

American (AMR) AF: 0.00 AC: 0 AN: 12

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1

East Asian (EAS) AF: 0.00 AC: 0 AN: 5

South Asian (SAS) AF: 0.00 AC: 0 AN: 1

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 389

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 10

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 143

Other (OTH) AF: 0.00 AC: 0 AN: 43

GnomAD4 genome AF: 0.00502 AC: 542 AN: 107952 Hom.: 4 Cov.: 20 AF XY: 0.00359 AC XY: 109 AN XY: 30394

African (AFR) AF: 0.0170 AC: 502 AN: 29588

American (AMR) AF: 0.00313 AC: 32 AN: 10219

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2598

East Asian (EAS) AF: 0.00 AC: 0 AN: 3407

South Asian (SAS) AF: 0.00 AC: 0 AN: 2434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.0000193 AC: 1 AN: 51799

Other (OTH) AF: 0.00480 AC: 7 AN: 1459

Alfa AF: 0.00477 Hom.: 12

Bravo AF: 0.00616

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.6
DANN	Benign	0.72
PhyloP100		0.027
PromoterAI		-0.069	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism

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: rs12008523; hg19: chrX-41192689;