rs1555954154

Positions:

• chrX-41346399-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3 PP5_Moderate

The NM_001356.5(DDX3X):​c.1486G>A​(p.Val496Met) 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: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 9.94

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain Helicase C-terminal (size 161) in uniprot entity DDX3X_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001356.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DDX3X. . Gene score misZ 4.3295 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked intellectual disability-hypotonia-movement disorder syndrome, Toriello-Carey syndrome, intellectual disability, X-linked 102, X-linked syndromic intellectual disability.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.83
• PP5: Variant X-41346399-G-A is Pathogenic according to our data. Variant chrX-41346399-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 548024.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-41346399-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDX3X	NM_001356.5	c.1486G>A	p.Val496Met	missense_variant	13/17	ENST00000644876.2	NP_001347.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX3X	ENST00000644876.2	c.1486G>A	p.Val496Met	missense_variant	13/17		NM_001356.5	ENSP00000494040	A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, X-linked 102 Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Observed in affected males w/de novo occurrence [Wang et al 2018, Nicola et al 2019] -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 07, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;.;D;D;D;D;D;D;D;D;D;D;D;.;.;D;.;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Pathogenic	3.6	H;H;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.9	.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	.;D;D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.88, 0.88, 0.78
MutPred		0.67		Gain of catalytic residue at V496 (P = 0.0702);Gain of catalytic residue at V496 (P = 0.0702);Gain of catalytic residue at V496 (P = 0.0702);Gain of catalytic residue at V496 (P = 0.0702);.;.;Gain of catalytic residue at V496 (P = 0.0702);.;Gain of catalytic residue at V496 (P = 0.0702);.;.;Gain of catalytic residue at V496 (P = 0.0702);.;.;.;.;.;.;.;
MVP		0.96
MPC		2.7
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555954154; hg19: chrX-41205652; COSMIC: COSV67863150; COSMIC: COSV67863150;