Variant classification summary

NM_016222.2:c.1479C>T

DDX41 · NP_057306.2:p.(Ser493=) · NM_016222.2

GRCh37: chr5:176939567 G>A · GRCh38: chr5:177512566 G>A

Gene: DDX41 Transcript: NM_016222.2

Final call

Likely Benign

BS1 strong BP7 supporting

Variant details

Gene

DDX41

Transcript

NM_016222.2

Protein

NP_057306.2:p.(Ser493=)

gnomAD AF

0.0002849751204329639 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BS1 (Strong): East Asian allele frequency 0.709% (gnomAD v4.1, 318/44,870 alleles, grpmax FAF 0.645%) far exceeds the >0.3% threshold expected for this rare, adult-onset disorder.

2

BP7 (Supporting): synonymous p.Ser493= with SpliceAI max delta 0.015 (below the 0.2 cutoff) at a non-conserved nucleotide that is a common East Asian polymorphism.

3

Overall: Likely Benign — one strong benign (BS1) plus one supporting benign (BP7) under the generic ACMG/AMP 2015 combination rules.

Final determination: Under the generic ACMG/AMP 2015 fallback (no usable VCEP framework), one strong benign criterion (BS1) plus one supporting benign criterion (BP7) yields Likely Benign; Benign would require BA1 alone or two strong benign criteria, neither of which is met.

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	Not applicable: c.1479C>T is synonymous (p.Ser493=), so no null-variant mechanism (nonsense-mediated decay or truncation) is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: synonymous p.Ser493= produces no amino acid change to compare against a previously pathogenic missense.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband, parental, or de novo genotyping data were available to evaluate this criterion.	PMID:25741868 cspec
PS3	Not assessed	Not assessed: no variant-specific functional assay evidence (RNA, minigene, or cellular) was available.	cspec PMID:25741868 spliceai oncokb clinvar
PS4	Not met	Not met: no case-control enrichment data exist, and the variant is common in East Asians (gnomAD v4.1 EAS AF 0.709%).	clinvar gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM1	N/A	Not applicable: synonymous p.Ser493= leaves no altered residue to evaluate for mutational-hotspot or critical-domain membership.	generic_acmg_combination_rules
PM2	Not met	Not met: gnomAD v4.1 East Asian allele frequency 0.709% far exceeds the <0.1% PM2 threshold on the max-population-AF basis.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
PM3	N/A	Not applicable: DDX41 predisposition is autosomal dominant, so the recessive in-trans requirement of PM3 does not apply.	cspec PMID:25741868
PM4	N/A	Not applicable: synonymous p.Ser493= causes no protein length change, so there is nothing for PM4 to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: p.Ser493= is not a missense change, so no comparison to a known pathogenic missense at this residue is possible.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no parental testing or proband data were available to support an assumed de novo origin.	PMID:25741868 cspec
PP1	Not assessed	Not assessed: no affected relatives were tested, so no co-segregation evidence was available.	PMID:25741868 cspec
PP2	N/A	Not applicable: missense-constraint properties are irrelevant because p.Ser493= is a synonymous change.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.015 is far below the 0.2 splice-alteration cutoff, and missense predictors do not apply.	spliceai PMID:25741868
PP4	Not assessed	Not assessed: no proband phenotype or family-history data were available.	clinvar cspec generic_acmg_combination_rules
PP5	Not met	Not met: ClinVar VCV000726954 contains no expert-panel pathogenic classification (0 of 4 submissions).	clinvar generic_acmg_combination_rules
BA1	Not met	Not met: highest subpopulation allele frequency 0.709% (gnomAD v4.1 EAS) falls below the >1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
BS1	Met	Met (strong): gnomAD v4.1 East Asian allele frequency 0.709% exceeds the >0.3% BS1 threshold for this rare, adult-onset disorder.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
BS2	N/A	Not applicable: DDX41 disease is adult-onset with incomplete, age-dependent penetrance, so BS2's early-onset, fully-penetrant requirement does not apply.	PMID:25741868
BS3	Not assessed	Not assessed: no well-established functional study of this synonymous variant was available.	cspec PMID:25741868 spliceai oncokb clinvar
BS4	Not assessed	Not assessed: no family testing data existed to document absence of segregation.	PMID:25741868 cspec
BP1	N/A	Not applicable: BP1 concerns missense variants, and p.Ser493= is a synonymous change.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no proband or family phase data (cis/trans with a pathogenic variant) were available.	cspec PMID:25741868 clinvar
BP3	N/A	Not applicable: p.Ser493= is not an in-frame indel, so no repeat-region length change exists to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: missense in-silico predictors (REVEL/BayesDel) do not apply to this synonymous variant.	cspec PMID:25741868
BP5	Not assessed	Not assessed: no proband data were available to identify an alternate molecular basis of disease.	generic_acmg_combination_rules
BP6	Not met	Not met: all 4 ClinVar submissions are ordinary clinical laboratories, with no expert-panel benign classification.	clinvar generic_acmg_combination_rules
BP7	Met	Met (supporting): synonymous p.Ser493= with SpliceAI max delta 0.015 (below the 0.2 cutoff) and a common, non-conserved East Asian polymorphism (AF 0.709%).	spliceai gnomad_v4 gnomad_v2 PMID:25741868

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