Variant X-41346376-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate

The NM_001356.5(DDX3X):c.1463G>C(p.Arg488Pro) 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 Pathogenic (★).

Frequency

Genomes: not found (cov: 22)

Consequence

DDX3X
NM_001356.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.94

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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, 0.957

PP5

Variant X-41346376-G-C is Pathogenic according to our data. Variant chrX-41346376-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1330240.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDX3X	NM_001356.5 linkuse as main transcript	c.1463G>C	p.Arg488Pro	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 linkuse as main transcript	c.1463G>C	p.Arg488Pro	missense_variant	13/17		NM_001356.5	ENSP00000494040	A1	O00571-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Intellectual disability, X-linked 102

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Oct 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;D;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

.;.;D;D;D;D;D;D;D;D;D;D;D;.;.;D;.;D;D

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.46

MutationAssessor

Pathogenic

3.9

H;H;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-6.4

.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Uncertain

0.027

.;D;D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Polyphen

0.95

P;P;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.92, 0.92, 0.92, 0.90

MutPred

0.76

Loss of catalytic residue at R488 (P = 0.0098);Loss of catalytic residue at R488 (P = 0.0098);Loss of catalytic residue at R488 (P = 0.0098);Loss of catalytic residue at R488 (P = 0.0098);.;.;Loss of catalytic residue at R488 (P = 0.0098);.;Loss of catalytic residue at R488 (P = 0.0098);.;.;Loss of catalytic residue at R488 (P = 0.0098);.;.;.;.;.;.;.;

MVP

0.97

MPC

3.3

ClinPred

1.0

GERP RS

5.4

Varity_R

0.98

gMVP

1.0

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over