NM_016222.4:c.435-2_435-1delAGinsCA

Variant names:

• chr5-177515822-CT-TG
• rs869320762
• NM_016222.4:c.435-2_435-1delAGinsCA

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 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. 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 (★★). ClinVar reports functional evidence for this variant: "SCV003439313: 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)." and additional evidence is available in ClinVar.

• 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: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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, ClinGen
• acromesomelic dysplasia

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 20 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.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV003439313: 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).; SCV005325839: 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); SCV006226531: 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).
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016222.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX41	NM_016222.4	MANE Select	c.435-2_435-1delAGinsCA		splice_acceptor intron	N/A	NP_057306.2
	DDX41	NM_001321732.2		c.57-2_57-1delAGinsCA		splice_acceptor intron	N/A	NP_001308661.1	B3KRK2
	DDX41	NM_001321830.2		c.57-2_57-1delAGinsCA		splice_acceptor intron	N/A	NP_001308759.1	B3KRK2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX41	ENST00000330503.12	TSL:1 MANE Select	c.435-2_435-1delAGinsCA		splice_acceptor intron	N/A	ENSP00000330349.8	Q9UJV9
	DDX41	ENST00000515562.1	TSL:1	n.702_703delAGinsCA		non_coding_transcript_exon	Exon 3 of 3
	DDX41	ENST00000507955.6	TSL:1	n.435-2_435-1delAGinsCA		splice_acceptor intron	N/A	ENSP00000422753.2	A0A499FJW5

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

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	Inborn genetic diseases (1)
-	-	-	DDX41-related hematologic malignancy predisposition syndrome (1)

Computational scores

Source: dbNSFP v4.9

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;