NM_016222.2:c.521A>G

DDX41 · NP_057306.2:p.(Asp174Gly) · NM_016222.2

GRCh37: chr5:176942736 T>C · GRCh38: chr5:177515735 T>C

Gene: DDX41 Transcript: NM_016222.2

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

DDX41

Transcript

NM_016222.2

Protein

NP_057306.2:p.(Asp174Gly)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The DDX41 c.521A>G (p.Asp174Gly, p.D174G) variant has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in the general population.

No reviewed variant-specific functional study was identified for this variant.

Available computational evidence argues against a damaging effect, with SpliceAI showing no significant splice impact (max delta score 0.14), REVEL 0.124, and BayesDel -0.387301.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This missense variant does not create a nonsense, frameshift, canonical ±1/2 splice, initiation-codon, or exon-level loss-of-function change. Although DDX41 loss of function is an established disease mechanism, c.521A>G does not fall within the generic PVS1 null-variant framework.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified showing that another nucleotide change produces the same amino acid substitution with an established pathogenic or likely pathogenic classification.	clinvar cspec
PS2	Not assessed	No confirmed de novo occurrence was identified for this variant. Parental relationship confirmation and parental testing data were not available.	clinvar cspec
PS3	Not assessed	No well-established functional study was identified for p.(Asp174Gly) demonstrating a damaging effect on DDX41 function.	oncokb
PS4	Not assessed	No case-control enrichment data or multiple affected probands carrying this specific variant were identified. Available evidence does not establish increased prevalence in affected individuals compared with controls.	clinvar gnomad_v2 gnomad_v4
PM1	Not assessed	Available evidence does not show that Asp174 lies in a well-established mutational hotspot or a defined critical functional region without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this residue, but domain-level evidence was limited.	hotspots cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity in the general population and meets PM2 at supporting strength.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is intended for recessive disorders with pathogenic variants observed in trans. The available DDX41 disease framework is autosomal dominant, so this criterion is not applicable.	cspec
PM4	N/A	This variant is a missense substitution and does not cause a protein length change from an in-frame insertion/deletion or stop-loss event.	cspec
PM5	N/A	Classic same-residue PM5 logic could not be confirmed safely for the governing framework, and no pathogenic same-residue comparator variants were identified. PM5 was therefore not applied.	pm5_candidates cspec
PM6	Not assessed	No apparently de novo occurrence without confirmed parentage was identified for this variant.	clinvar cspec
PP1	Not assessed	No segregation data were identified showing that this variant tracks with DDX41-related hematologic malignancy predisposition in affected relatives.	clinvar cspec
PP2	Not assessed	Available evidence does not establish a gene-specific rule that missense variation is a common pathogenic mechanism for DDX41 and that benign missense variation is uncommon.	cspec
PP3	Not met	Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.14, REVEL is low at 0.124, and BayesDel is negative at -0.387301.	spliceai revel bayesdel
PP4	Not assessed	No individual clinical phenotype or family history data were provided to determine whether the presentation is highly specific for DDX41-related disease.	cspec
PP5	N/A	PP5 is not applied because no reputable-source pathogenic assertion without accessible supporting evidence was used.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and v4.1 and is therefore below the stand-alone benign frequency threshold of 1%.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and v4.1 and is therefore below the strong benign frequency threshold of 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals at a frequency sufficient to argue against pathogenicity.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study was identified showing normal DDX41 function for p.(Asp174Gly).	oncokb
BS4	Not assessed	No non-segregation data were identified for this variant. In addition, reduced and age-related penetrance can complicate interpretation of unaffected relatives in DDX41-related disease.	cspec
BP1	Not assessed	Available evidence does not establish that missense variation is generally a benign or uncommon disease mechanism in DDX41 sufficient to support BP1 for this missense change.	cspec
BP2	Not assessed	No phase information or second-variant data were identified to assess occurrence in trans with a pathogenic variant or in cis with another variant.	cspec
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions without known function, which does not match this missense substitution.	cspec
BP4	Met	Multiple computational predictors argue against a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.14, REVEL is low at 0.124, and BayesDel is negative at -0.387301, supporting BP4.	spliceai revel bayesdel
BP5	Not assessed	No alternate molecular diagnosis or alternate established cause for the observed phenotype was provided to support BP5.	cspec
BP6	N/A	BP6 is not applied because no reputable-source benign assertion without accessible supporting evidence was used.	clinvar
BP7	N/A	BP7 applies to synonymous or intronic variants with no predicted splice impact. This variant is a missense substitution, so BP7 is not applicable.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.