dbSNP rs1555953882: DDX3X:p.Asp426AsnfsTer9 (chrX-41345506-TCAGA-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001356.5(DDX3X):c.1276_1279delGACA(p.Asp426AsnfsTer9) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,095,851 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. D426D) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

DDX3X
NM_001356.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.87

Publications

0 publications found

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:

RN7SL15P (HGNC:46031): (RNA, 7SL, cytoplasmic 15, pseudogene)

RN7SL15P links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-41345506-TCAGA-T is Pathogenic according to our data. Variant chrX-41345506-TCAGA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 520543.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 link	c.1276_1279delGACA	p.Asp426AsnfsTer9	frameshift_variant	Exon 12 of 17	ENST00000644876.2	NP_001347.3	O00571-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX3X	ENST00000644876.2 link	c.1276_1279delGACA	p.Asp426AsnfsTer9	frameshift_variant	Exon 12 of 17		NM_001356.5	ENSP00000494040.1		O00571-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.13e-7

AC:

AN:

1095851

Hom.:

AF XY:

0.00

AC XY:

AN XY:

361323

show subpopulations

African (AFR)

AF:

0.0000380

AC:

AN:

26302

American (AMR)

AF:

0.00

AC:

AN:

34758

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19309

East Asian (EAS)

AF:

0.00

AC:

AN:

30189

South Asian (SAS)

AF:

0.00

AC:

AN:

53495

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40502

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4114

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841165

Other (OTH)

AF:

0.00

AC:

AN:

46017

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Sep 29, 2015

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.9

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over