rs1267519974

chrX-41344084-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001356.5(DDX3X):c.820C>T(p.Pro274Ser) 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. 13/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: DDX3X NM_001356.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.52

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain Helicase ATP-binding (size 192) in uniprot entity DDX3X_HUMAN there are 45 pathogenic changes around while only 1 benign (98%) in NM_001356.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DDX3X
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant X-41344084-C-T is Pathogenic according to our data. Variant chrX-41344084-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559641.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDX3X	NM_001356.5	c.820C>T	p.Pro274Ser	missense_variant	9/17	ENST00000644876.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDX3X	ENST00000644876.2	c.820C>T	p.Pro274Ser	missense_variant	9/17		NM_001356.5	A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, X-linked 102 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Mar 28, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	T;T;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.040	D
MutationAssessor	Pathogenic	3.5	H;H;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
Polyphen		1.0	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.95, 0.95, 0.94, 0.84
MutPred		0.92		Gain of MoRF binding (P = 0.0494);Gain of MoRF binding (P = 0.0494);Gain of MoRF binding (P = 0.0494);Gain of MoRF binding (P = 0.0494);.;Gain of MoRF binding (P = 0.0494);.;Gain of MoRF binding (P = 0.0494);.;.;Gain of MoRF binding (P = 0.0494);.;.;.;.;.;.;.;
MVP		0.96
MPC		2.7
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs1267519974; hg19: chrX-41203337; COSMIC: COSV105335046; COSMIC: COSV105335046;