rs1555953796

Variant names:

• chrX-41345187-G-C
• rs1555953796
• NM_001356.5:c.1033G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001356.5(DDX3X):​c.1033G>C​(p.Val345Leu) variant causes a missense 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: 23)
• Consequence: DDX3X NM_001356.5 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 8.08
• 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: Likely_pathogenic. The variant received 9 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, 5 uncertain in NM_001356.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 93 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Gene score misZ: 4.3295 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, X-linked 102, X-linked syndromic intellectual disability, Toriello-Carey syndrome, X-linked intellectual disability-hypotonia-movement disorder syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• PP5: Variant X-41345187-G-C is Pathogenic according to our data. Variant chrX-41345187-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 438761.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDX3X	NM_001356.5	c.1033G>C	p.Val345Leu	missense_variant	Exon 11 of 17	ENST00000644876.2	NP_001347.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX3X	ENST00000644876.2	c.1033G>C	p.Val345Leu	missense_variant	Exon 11 of 17		NM_001356.5	ENSP00000494040.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Medulloblastoma Other:1

May 01, 2016

Donald Williams Parsons Laboratory, Baylor College of Medicine

Significance: other

Review Status: no assertion criteria provided

Collection Method: clinical testing

- 3: Mutations in other consensus cancer genes, not currently considered targetable

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	.;.;D;D;D;D;D;D;D;D;D;D;D;.;.;D;.;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.0094	D
MutationAssessor	Pathogenic	3.7	H;H;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		8.1
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.6	.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0060	.;D;D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.93	P;P;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.59, 0.58, 0.59, 0.59
MutPred		0.81		Loss of methylation at K342 (P = 0.0876);Loss of methylation at K342 (P = 0.0876);Loss of methylation at K342 (P = 0.0876);Loss of methylation at K342 (P = 0.0876);.;.;Loss of methylation at K342 (P = 0.0876);.;Loss of methylation at K342 (P = 0.0876);.;.;Loss of methylation at K342 (P = 0.0876);.;.;.;.;.;.;.;
MVP		0.89
MPC		2.5
ClinPred		1.0	D
GERP RS		5.4
PromoterAI		-0.00040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.99
Mutation Taster		=13/87	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555953796; hg19: chrX-41204440; COSMIC: COSV67864211;