rs1555950665

Variant names:

• chrX-41334255-G-A
• rs1555950665
• NM_001356.5:c.3G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-41334255-G-A
• chrX-41334255-G-C
• chrX-41334255-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001356.5(DDX3X):​c.3G>A​(p.Met1?) variant causes a start lost 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: 24)
• Consequence: DDX3X NM_001356.5 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.44
• 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

ENSG00000301689 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 64 pathogenic variants. Next in-frame start position is after 187 codons. Genomic position: 41343231. Lost 0.281 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-41334255-G-A is Pathogenic according to our data. Variant chrX-41334255-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1921343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDX3X	NM_001356.5	c.3G>A	p.Met1?	start_lost	Exon 1 of 17	ENST00000644876.2	NP_001347.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX3X	ENST00000644876.2	c.3G>A	p.Met1?	start_lost	Exon 1 of 17		NM_001356.5	ENSP00000494040.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

May 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the DDX3X protein in which other variant(s) (p.Tyr38Cys) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Disruption of the initiator codon has been observed in individual(s) with DDX3X-related conditions (PMID: 33993884). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the DDX3X mRNA. The next in-frame methionine is located at codon 187. -

DDX3X-related disorder Pathogenic:1

Jun 07, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DDX3X c.3G>A variant is predicted to disrupt the translation initiation site (Start Loss). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note, another variant disrupting the initiating methionine codon of DDX3X (c.3G>C), was reported as de novo in a female patient with DDX3X syndrome (Patient DDX1 in Table S1 in Tang. 2021. PubMed ID: 33993884). Based on this evidence, we interpret the c.3G>A (Start Loss) variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;T;.;T;.;.;.;.;.;.;.;.;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	.;.;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
PhyloP100		8.4
PROVEAN	Benign	-1.9	.;.;.;.;N;.;D;.;.;.;.;N;.
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	.;.;.;.;D;.;.;.;.;.;.;D;.
Sift4G	Pathogenic	0.0	.;D;D;D;D;.;D;.;.;.;.;D;.
Polyphen		0.27	B;B;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.83, 0.85, 0.84, 0.83, 0.89, 0.83
MutPred		0.98		Gain of catalytic residue at M1 (P = 0.0149);Gain of catalytic residue at M1 (P = 0.0149);Gain of catalytic residue at M1 (P = 0.0149);Gain of catalytic residue at M1 (P = 0.0149);Gain of catalytic residue at M1 (P = 0.0149);Gain of catalytic residue at M1 (P = 0.0149);Gain of catalytic residue at M1 (P = 0.0149);Gain of catalytic residue at M1 (P = 0.0149);Gain of catalytic residue at M1 (P = 0.0149);Gain of catalytic residue at M1 (P = 0.0149);Gain of catalytic residue at M1 (P = 0.0149);Gain of catalytic residue at M1 (P = 0.0149);Gain of catalytic residue at M1 (P = 0.0149);
MVP		0.98
ClinPred		0.98	D
GERP RS		4.3
PromoterAI		-0.032	Neutral
Varity_R		0.50
gMVP		0.45
Mutation Taster		=2/198	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1555950665; hg19: chrX-41193508;