chrX-41333711-G-C

Variant names:

• chrX-41333711-G-C
• rs186005081
• ENST00000478993.5:n.-542G>C

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.-542G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 102,571 control chromosomes in the GnomAD database, including 25 homozygotes. There are 315 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (25 hom., 315 hem., cov: 22)
  • 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: -1.61
• 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=-0.76).
• BP6: Variant X-41333711-G-C is Benign according to our data. Variant chrX-41333711-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1216001.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0136 (1395/102571) while in subpopulation AFR AF = 0.0472 (1322/27983). AF 95% confidence interval is 0.0451. There are 25 homozygotes in GnomAd4. There are 315 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 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.404G>C		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.-542G>C		non_coding_transcript_exon	Exon 1 of 19	ENSP00000478443.1	O00571-1
	DDX3X	ENST00000478993.5	TSL:1	n.-542G>C		5_prime_UTR	Exon 1 of 19	ENSP00000478443.1	O00571-1
	DDX3X	ENST00000625837.2	TSL:5	c.-542G>C		5_prime_UTR	Exon 1 of 19	ENSP00000486306.1	A0A0D9SF53

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 1393 AN: 102552 Hom.: 25 Cov.: 22

Gnomad AFR AF: 0.0472

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00492

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: 0.000340

Gnomad OTH AF: 0.00665

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 991 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 429

African (AFR) AF: 0.00 AC: 0 AN: 11

American (AMR) AF: 0.00 AC: 0 AN: 26

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7

East Asian (EAS) AF: 0.00 AC: 0 AN: 15

South Asian (SAS) AF: 0.00 AC: 0 AN: 275

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 193

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 428

Other (OTH) AF: 0.00 AC: 0 AN: 34

GnomAD4 genome AF: 0.0136 AC: 1395 AN: 102571 Hom.: 25 Cov.: 22 AF XY: 0.0112 AC XY: 315 AN XY: 28055

African (AFR) AF: 0.0472 AC: 1322 AN: 27983

American (AMR) AF: 0.00492 AC: 47 AN: 9556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2524

East Asian (EAS) AF: 0.00 AC: 0 AN: 3262

South Asian (SAS) AF: 0.00 AC: 0 AN: 2388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 202

European-Non Finnish (NFE) AF: 0.000340 AC: 17 AN: 50020

Other (OTH) AF: 0.00657 AC: 9 AN: 1369

Alfa AF: 0.000289 Hom.: 1

Bravo AF: 0.0148

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	-0.76
CADD	Benign	1.5
DANN	Benign	0.55
PhyloP100		-1.6
PromoterAI		0.0066	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs186005081; hg19: chrX-41192964;