chr5-177515822-CT-TG

Position:

• chr5-177515822-CT-TG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_016222.4(DDX41):​c.435-2_435-1delAGinsCA variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DDX41 NM_016222.4 splice_acceptor, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.63

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-177515822-CT-TG is Pathogenic according to our data. Variant chr5-177515822-CT-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDX41	NM_016222.4	c.435-2_435-1delAGinsCA		splice_acceptor_variant, intron_variant		ENST00000330503.12	NP_057306.2
DDX41	NM_001321732.2	c.57-2_57-1delAGinsCA		splice_acceptor_variant, intron_variant			NP_001308661.1
DDX41	NM_001321830.2	c.57-2_57-1delAGinsCA		splice_acceptor_variant, intron_variant			NP_001308759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX41	ENST00000330503.12	c.435-2_435-1delAGinsCA		splice_acceptor_variant, intron_variant		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:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 16, 2023	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. Studies have shown that disruption of this splice site results in skipping of exon 6 and/or partial retention of intron 6 and introduces a premature termination codon (PMID: 26712909). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 224636). Disruption of this splice site has been observed in individual(s) with DDX41-related conditions (PMID: 26712909, 32054657). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. 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 disrupted protein product. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 04, 2015	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2024	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) -

DDX41-related hematologic malignancy predisposition syndrome Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Mar 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs869320762; hg19: chr5-176942823;