rs869320762

Variant names:

• chr5-177515822-CT-TG
• rs869320762
• ENST00000515562.1:n.702_703delAGinsCA

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3 PP5_Very_Strong

The ENST00000515562.1(DDX41):​n.702_703delAGinsCA variant causes a non coding transcript exon change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DDX41 ENST00000515562.1 non_coding_transcript_exon
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.63
• Publications: 0 publications found

Genes affected

DDX41 (HGNC:18674): (DEAD-box helicase 41) DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure, such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of the DEAD box protein family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. The protein encoded by this gene is a member of the DEAD box protein family and interacts with several spliceosomal proteins. In addition, the encoded protein may recognize the bacterial second messengers cyclic di-GMP and cyclic di-AMP, resulting in the induction of genes involved in the innate immune response. [provided by RefSeq, Jan 2017]

DDX41 Gene-Disease associations (from GenCC):

• DDX41-related hematologic malignancy predisposition syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen, Ambry Genetics
• acromesomelic dysplasia

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 5-177515822-CT-TG is Pathogenic according to our data. Variant chr5-177515822-CT-TG is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 224636.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
DDX41	NM_016222.4	c.435-2_435-1delAGinsCA		splice_acceptor_variant, intron_variant	Intron 5 of 16	ENST00000330503.12	NP_057306.2
DDX41	NM_001321732.2	c.57-2_57-1delAGinsCA		splice_acceptor_variant, intron_variant	Intron 4 of 15		NP_001308661.1
DDX41	NM_001321830.2	c.57-2_57-1delAGinsCA		splice_acceptor_variant, intron_variant	Intron 5 of 16		NP_001308759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX41	ENST00000330503.12	c.435-2_435-1delAGinsCA		splice_acceptor_variant, intron_variant	Intron 5 of 16	1	NM_016222.4	ENSP00000330349.8

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Dec 04, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the canonical acceptor splice site of intron 5 and is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated DDX41 protein with potentially abnormal function. This sequence change appears to be novel and does not appear to have been described in patients or the normal population databases. This sequence change is predicted to be likely pathogenic, however functional studies have not been performed to prove this conclusively. This patient is a carrier of this likely pathogenic sequence change in DDX41. Germline mutations in DDX41 are associated with the development of hereditary myelodysplastic syndrome and acute myeloid leukemia. Our interpretation is based on the current understanding of the genetics of DDX41-related myeloid neoplasms. -

Jul 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a splice site in intron 5 of the DDX41 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. Disruption of this splice site has been observed in individual(s) with DDX41-related conditions (PMID: 26712909, 32054657, 33850299). ClinVar contains an entry for this variant (Variation ID: 224636). Studies have shown that disruption of this splice site results in skipping of exon 6 and/or partial retention of intron 6, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 26712909). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jan 14, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant demonstrated to result in aberrant splicing resulting in a null allele in a gene for which loss of function is a known mechanism of disease (PMID: 26712909); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28637623, 32054657, 26712909, 33850299) -

Inborn genetic diseases Pathogenic:1

Apr 25, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.435-2_435-1delAGinsCA intronic variant, located in intron 5 of the DDX41 gene, results from an in-frame from the deletion of two nucleotides and the insertion of two nucleotides at nucleotide position 435. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). An RT-PCR assay demonstrated that this variant leads to exon 6 skipping and/or partial retention of intron 6 and 7, resulting in an out-of-frame transcript (Lewinsohn M et al. Blood, 2016 Feb;127:1017-23). This variant was reported in individual(s) with features consistent with DDX41-related hematologic malignancy predisposition syndrome (Singhal D et al. Leukemia, 2021 Nov;35:3245-3256; Lewinsohn M et al. Blood, 2016 Feb;127:1017-23; Blombery P et al. Haematologica, 2021 Jan;106:64-73). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

DDX41-related hematologic malignancy predisposition syndrome Other:1

Mar 16, 2023

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=10/90	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs869320762; hg19: chr5-176942823;