DDX41 c.1088_1090del, p.Ser363del
NM_016222.2:c.1088_1090del
Variant of Uncertain Significance (VUS)
The S363del variant in DDX41 is classified as Variant of Uncertain Significance based on moderate evidence of rarity and protein length change (PM2, PM4) counterbalanced by supportive benign computational evidence (BP4), with no additional data to fulfill either pathogenic or benign criteria.
ACMG/AMP Criteria Applied
PM2
PM4
BP4
Genetic Information
Gene & Transcript Details
Gene
DDX41
Transcript
NM_016222.4
MANE Select
Total Exons
17
Strand
Reverse (−)
Reference Sequence
NC_000005.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_016222.2 | Alternative | 17 exons | Reverse |
| NM_016222.3 | Alternative | 17 exons | Reverse |
Variant Details
HGVS Notation
NM_016222.2:c.1088_1090del
Protein Change
S363del
Location
Exon 10
(Exon 10 of 17)
5'Exon Structure (17 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_016222.4
Genome Browser
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HGVS InputNM_016222:c.1088_1090del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000398%
Extremely Rare
Highest in Population
African/African American
0.00616%
Rare
Global: 0.000398%
African/African American: 0.00616%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251030Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000398%, 1/251030 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.00616%, 1/16230 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
3 publications
Likely Pathogenic
Based on 7 submitter reviews in ClinVar
Submitter Breakdown
2 Path
1 LP
4 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (3)
This variant, c.1088_1090del, results in the deletion of 1 amino acid(s) of the DDX41 protein (p.Ser363del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has been observed in individual(s) with acute myeloid leukemia and/or hematological malignancies (PMID: 31484648, 35443031, 35671390, 36322930). ClinVar contains an entry for this variant (Variation ID: 2500218). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
The c.1088_1090delCCT variant (also known as p.S363del) is located in coding exon 10 of the DDX41 gene. This variant results from an in-frame CCT deletion at nucleotide positions 1088 to 1090. This results in the in-frame deletion of a serine at codon 363. This variant has been reported in individuals with hematologic malignancy (Sébert M et al. Blood, 2019 Oct;134:1441-1444; Perani A et al. Front Oncol, 2023 Feb;13:1120829; Makishima H et al. Blood, 2023 Feb;141:534-549). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this variant remains unclear.
The variant DDX41(NM_016222.4):c.1088_1090del:p.(Ser363del) is very rare in control population database. It has been raported in individuals with suspected or confirmed predisposition to myeloid malignancies (Duployez et al, 2022, PMID: 35443031; Makishima et al, 2022, PMID: 36322930; Perani et al, 2023, PMID: 36923434; Sebert et al, 2019, PMID: 31484648) and notably in association with a second (somatic) DDX41 hit, which is a common clonal evolution way in DDX41-myeloid malignancies predisposition (Duployez et al, 2022, PMID: 35443031).
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Pathogenic (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.83
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant (nonsense, frameshift, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows: an in-frame deletion of a single amino acid (S363del), which does not create a null allele. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: no report of S363del caused by a different nucleotide change classified as pathogenic. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no information on de novo occurrence with parental confirmation. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows: no functional characterization data. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls." The evidence for this variant shows: no case-control or cohort data available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or well-studied functional domain, without benign variation." The evidence for this variant shows: no data placing S363del in a known hot spot or critical domain. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium." The evidence for this variant shows: an extremely low population frequency (gnomAD MAF 0.000398%, no homozygotes). Therefore, this criterion is applied at Moderate strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: DDX41‐related disease is not a recessive disorder with trans configuration, and no trans data exist. Therefore, this criterion is not applied.
PM4
PM4 (Moderate)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in a nonrepeat region or stop-loss variants." The evidence for this variant shows: an in-frame deletion of a single amino acid (S363del) outside of a known repetitive region. Therefore, this criterion is applied at Moderate strength.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." The evidence for this variant shows: S363del is not a novel missense and no pathogenic missense at residue 363 is reported. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no assumptions or data regarding de novo origin. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease." The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence for this variant shows: the change is an in-frame deletion, not a missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product." The evidence for this variant shows: in silico predictors are benign (CADD 2.83) and SpliceAI predicts no splicing impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no specific phenotype or clinical context provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: conflicting ClinVar assertions (Uncertain, Pathogenic, Likely Pathogenic). Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium." The evidence for this variant shows: MAF 0.000398%, far below 5%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder." The evidence for this variant shows: population frequency is very low and not above expected thresholds. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant (with full penetrance expected at an early age), X-linked or mitochondrial disorder with full penetrance expected at an early age." The evidence for this variant shows: no reports in healthy adults. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing." The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected members of a family." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in gene for which primarily truncating variants are known to cause disease." The evidence for this variant shows: this is an in-frame deletion, not missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder." The evidence for this variant shows: no trans observations with a pathogenic variant. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: S363del is not within a known repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)." The evidence for this variant shows: computational predictors (CADD 2.83) and SpliceAI (max 0.02) predict no deleterious effect. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no alternate molecular diagnosis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: no reputable benign assertion. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted splice impact and no conserved splice region." The evidence for this variant shows: this is an in-frame deletion, not synonymous. Therefore, this criterion is not applied.