NM_016222.2:c.1589G>A

DDX41 · NP_057306.2:p.(Gly530Asp) · NM_016222.2

GRCh37: chr5:176939355 C>T · GRCh38: chr5:177512354 C>T

Gene: DDX41 Transcript: NM_016222.2

Final call

VUS

PM2_Moderate PP3_Supporting

Variant details

Gene

DDX41

Transcript

NM_016222.2

Protein

NP_057306.2:p.(Gly530Asp)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The DDX41 c.1589G>A (p.Gly530Asp) variant has been observed in somatic cancers in COSMIC (COSV57250947, 4 occurrences) and has been reported in ClinVar as a variant of uncertain significance from 4 clinical laboratory submissions.

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

In silico data support a damaging missense effect, with a REVEL score of 0.901, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.03.

Final determination: The combination of PM2 at moderate strength and PP3 at supporting strength does not meet ACMG/AMP thresholds for either likely pathogenic or likely benign classification; therefore, this variant is classified as of uncertain significance.

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 is a missense variant, p.(Gly530Asp), and does not create a predicted null effect such as a nonsense, frameshift, canonical splice, initiation-codon, or exon-level loss-of-function change, so PVS1 is not applicable.	prefetch cspec
PS1	Not assessed	No evidence was identified that a different nucleotide change causing the same amino acid substitution, p.(Gly530Asp), is already established as pathogenic or likely pathogenic, so PS1 was not assessed.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with established maternity and paternity was identified, so PS2 was not assessed.
PS3	Not assessed	No well-established functional study demonstrating a damaging effect of p.(Gly530Asp) on DDX41 function was identified, so PS3 was not assessed.	PMID:26712909 PMID:34644397 PMID:37199125
PS4	Not met	This variant has been observed in somatic cancers in COSMIC (COSV57250947, n=4) and is listed in ClinVar as Uncertain significance, but no case-control enrichment or clearly quantified excess in unrelated individuals with DDX41-related hematologic malignancy predisposition was identified, so PS4 is not met.	cosmic clinvar PMID:26712909 PMID:34644397 PMID:37199125
PM1	Not met	This variant has not been shown to lie in a well-established mutational hotspot or a critical domain without benign variation; Cancer Hotspots did not identify a statistically significant hotspot at residue G530, so PM1 is not met.	hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, corresponding to an observed population frequency of 0, which is below the 0.1% rarity threshold used for PM2 support in this workflow and is consistent with rarity in the general population.	gnomad_v2 gnomad_v4
PM3	N/A	The available disease framework for DDX41-related hematologic malignancy predisposition is autosomal dominant, so the recessive trans observations required for PM3 are not applicable.	cspec prefetch
PM4	N/A	This is a single amino acid substitution and does not produce a protein length change from an in-frame insertion, deletion, or stop-loss event, so PM4 is not applicable.	prefetch
PM5	Not assessed	No evidence was identified that a different missense change at codon 530 is already established as pathogenic or likely pathogenic, so PM5 was not assessed.	clinvar
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified, so PM6 was not assessed.
PP1	Not assessed	No segregation data were identified showing this variant tracking with DDX41-related hematologic malignancy predisposition in a family, so PP1 was not assessed.	PMID:26712909 PMID:34644397 PMID:37199125
PP2	Not assessed	Available evidence was insufficient to determine whether missense variation is a well-established pathogenic mechanism for DDX41 with a sufficiently low benign missense rate to support PP2, so PP2 was not assessed.	cspec
PP3	Met	Computational evidence supports a deleterious protein effect for this missense change: REVEL is 0.901, while SpliceAI shows no meaningful splice disruption with a maximum delta score of 0.03. Taken together, these data support PP3 for a damaging missense effect rather than a splice mechanism.	spliceai prefetch
PP4	Not assessed	No individual-level phenotype, tumor, or family history details were identified that are sufficiently specific for DDX41-related hematologic malignancy predisposition to support PP4, so PP4 was not assessed.
PP5	N/A	PP5 was not applied because assertions from external sources without independently evaluable evidence are not used for current ACMG/AMP interpretation.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, giving an observed population frequency of 0, which is below the 1% threshold required for BA1, so BA1 is not met.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, giving an observed population frequency of 0, which is below the 0.3% threshold used for BS1 in this workflow, so BS1 is not met.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in well-phenotyped healthy adults at a frequency sufficient to argue against pathogenicity, so BS2 was not assessed.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study demonstrating normal DDX41 function for p.(Gly530Asp) was identified, so BS3 was not assessed.	PMID:26712909 PMID:34644397 PMID:37199125
BS4	Not assessed	No segregation data were identified showing lack of cosegregation of this variant with disease in informative relatives, so BS4 was not assessed.
BP1	Not assessed	Available evidence was insufficient to conclude that missense variation is an uncommon disease mechanism for DDX41 relative to truncating variants, so BP1 was not assessed.	cspec
BP2	N/A	The available disease framework for DDX41-related hematologic malignancy predisposition is autosomal dominant, so the recessive-phase evidence usually used for BP2 is not applicable here.	cspec prefetch
BP3	Not assessed	No evidence was identified that this amino acid change falls within a repetitive region or a region without known function where in-frame variation is typically tolerated, so BP3 was not assessed.
BP4	Not met	Computational data do not support a benign effect overall. Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, REVEL is 0.901 and supports a damaging missense effect, so BP4 is not met.	spliceai prefetch
BP5	Not assessed	No alternate molecular explanation was identified that would account for the phenotype independently of this variant, so BP5 was not assessed.
BP6	N/A	BP6 was not applied because external benign assertions without independently evaluable evidence are not used for current ACMG/AMP interpretation.	clinvar
BP7	N/A	This is a missense variant rather than a synonymous or deep intronic change, so BP7 is not applicable.	prefetch

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