NM_016222.2:c.1480_1496dup

DDX41 · NP_057306.2:p.(Ala500ArgfsTer52) · NM_016222.2

GRCh37: chr5:176939549 A>AGGGAAGTCCAGGCCCTT · GRCh38: chr5:177512548 A>AGGGAAGTCCAGGCCCTT

Gene: DDX41 Transcript: NM_016222.2

Final call

Likely Pathogenic

PVS1_Strong PM2_Supporting

Variant details

Gene

DDX41

Transcript

NM_016222.2

Protein

NP_057306.2:p.(Ala500ArgfsTer52)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_016222.2:c.1480_1496dup is a frameshifting duplication predicted to produce p.(Ala500ArgfsTer52) [p.(A500Rfs*52)], altering the reading frame from codon 500 and truncating the normal C-terminal portion of DDX41; this is consistent with a loss-of-function effect in a gene for which loss of function has been implicated in DDX41-related hematologic malignancy predisposition syndrome.

The variant is absent from gnomAD v2.1 and is seen once in gnomAD v4.1 at AF 6.84053e-07 (1/1,461,874 alleles), with highest observed population AF 8.99276e-07 in non-Finnish Europeans, supporting marked rarity in population databases.

Because the predicted premature termination occurs in the terminal exon, the available loss-of-function evidence is most appropriately weighted below full very-strong strength, and no additional independently curated case-level or functional evidence in the supplied materials upgrades the variant beyond the likely pathogenic range.

Overall, the available evidence supports classification of NM_016222.2:c.1480_1496dup (DDX41 p.(Ala500ArgfsTer52)) as Likely Pathogenic.

Final determination:

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	Met	NM_016222.2:c.1480_1496dup is a frameshifting duplication predicted to produce p.(Ala500ArgfsTer52)/p.(A500Rfs*52). VariantValidator places the change in exon 14, the last exon, so nonsense-mediated decay is not expected; however, the variant removes and replaces a substantial C-terminal portion of the normal protein. DDX41 loss of function is an established disease mechanism for DDX41-related hematologic malignancy predisposition, so generic ACMG PVS1 is applicable but conservatively downgraded to Strong for a terminal-exon truncating event.	oncokb PMID:26712909 PMID:36322930
PS1	Not assessed	No same-amino-acid pathogenic variant comparison was documented for this frameshift duplication.
PS2	Not assessed	No confirmed de novo data were provided.
PS3	Not assessed	The screened functional literature supports DDX41 biology but does not provide a variant-specific, well-established functional assay for NM_016222.2:c.1480_1496dup.	PMID:33651979 PMID:36322930
PS4	Not assessed	ClinVar lists the variant as Pathogenic, but the workspace does not provide independently curated proband counts or case-control data sufficient to score PS4.	clinvar
PM1	N/A	This is a truncating frameshift variant, and the workspace did not identify a statistically significant hotspot at residue Ala500.
PM2	Met	The variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 at AF 6.84053e-07 (1/1,461,874 alleles), with highest observed population AF 8.99276e-07 in non-Finnish Europeans; this supports rarity and is well below generic ACMG rarity cutoffs.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable for this autosomal dominant disorder context.	cspec
PM4	N/A	PM4 was not applied because the protein-length altering effect is already captured by PVS1 for this loss-of-function frameshift.
PM5	Not assessed	PM5 is not informative for this frameshift duplication.
PM6	Not assessed	No assumed de novo evidence was provided.
PP1	Not assessed	No segregation data were provided.
PP2	N/A	PP2 is a missense-focused criterion and is not applicable to this frameshift duplication.
PP3	N/A	PP3 was not applied because this is a frameshifting duplication rather than a missense or splice-region variant with interpretable in silico thresholds in the workspace.
PP4	Not assessed	No phenotype-specific case data were provided for the tested individual.
PP5	N/A	PP5 was not used because reputable-source assertions are not applied as independent evidence under current ClinGen practice.	clinvar
BA1	Not met	The observed gnomAD v4.1 AF of 6.84053e-07 is far below any stand-alone benign frequency threshold.	gnomad_v4
BS1	Not met	The observed gnomAD v4.1 AF of 6.84053e-07 and highest population AF of 8.99276e-07 are far below benign strong frequency ranges.	gnomad_v4
BS2	Not assessed	No evidence of the variant in well-phenotyped unaffected adults was provided.
BS3	Not assessed	No variant-specific well-established functional studies demonstrating normal function were provided.	PMID:33651979
BS4	Not assessed	No segregation-against-disease data were provided.
BP1	N/A	BP1 is a missense-specific benign criterion and is not applicable to this truncating frameshift variant.
BP2	Not assessed	No phase data or second pathogenic variant data were provided.
BP3	Not assessed	No evidence indicates that this duplication lies within a benign repetitive region without known function.
BP4	N/A	BP4 was not applied because this is a frameshifting duplication and no benign in silico evidence was provided.
BP5	Not assessed	No alternate molecular explanation for the phenotype was provided.
BP6	N/A	BP6 was not used because external assertions without shared evidence are not applied as independent evidence under current ClinGen practice.
BP7	N/A	BP7 is a synonymous/intronic criterion and is not applicable to this coding frameshift duplication.

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