Classification rationale

BS1BP7 Likely Benign

DDX41 c.1479C>T synonymous · exon 14

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

BS1 + BP7 → Likely Benign

Gene diagram · NM_016222.2 · variants mapped to exon structure

DDX41 NM_016222.2

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 15 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

BS1 strong review Benign

Met (strong): gnomAD v4.1 East Asian allele frequency 0.709% exceeds the >0.3% BS1 threshold for this rare, adult-onset disorder.

gnomAD v4.1: EAS AF 0.00708714 (318/44,870 alleles, 2 homozygotes); grpmax FAF 0.00644595; total AF 0.000284975 (460/1,614,176)gnomAD v2.1: EAS AF 0.00846948 (169/19,954 alleles, 0 homozygotes); grpmax FAF 0.00759882; total AF 0.000717867 (203/282,782)gnomAD-Canada v1.0: EAS AF 0.0149477 (20/1,338 alleles, 1 homozygote); total AF 0.0014658 (27/18,420)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗PMID:25741868 ↗

✓

BP7 supporting Benign

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 Lookup (source key: spliceai): max delta score 0.015 (DS_AG 0.015, DS_AL 0.014, DS_DG 0.003, DS_DL 0.002) for NM_016222.2:c.1479C>T, below the recommended 0.2 clinical threshold for predicting splice alteration (Jaganathan et al. 2019, Nature Genetics, PMID 30661751); nearest splice-site distances (DP_AG -28, DP_AL -150, DP_DG 220, DP_DL 264) place the variant outside the splice consensus, and no new acceptor/donor gain is predicted.The variant is synonymous: NM_016222.2:c.1479C>T, NP_057306.2:p.(Ser493=), exon 14 of DDX41; gnomAD-Canada VEP annotation is 'synonymous_variant' (source key: gnomad_canada).Nucleotide not highly conserved: gnomAD v4.1 (source key: gnomad_v4) total AF 0.000285 with East Asian AF 0.00709 (318/44870 alleles, 2 homozygotes); gnomAD v2.1 (source key: gnomad_v2) East Asian AF 0.00847 (169/19954 alleles, 0 homozygotes). A common East Asian polymorphism with observed homozygotes indicates the position tolerates variation, satisfying the BP7 non-conservation component.

spliceai ↗gnomad_v4 ↗gnomad_v2 ↗PMID:25741868 ↗

Assessed · not applied

Pathogenic

PS2 Not assessed: no proband, parental, or de novo genotyping data were available to evaluate this criterion.

PS3 Not assessed: no variant-specific functional assay evidence (RNA, minigene, or cellular) was available.

PS4 Not met: no case-control enrichment data exist, and the variant is common in East Asians (gnomAD v4.1 EAS AF 0.709%).

PM2 Not met: gnomAD v4.1 East Asian allele frequency 0.709% far exceeds the <0.1% PM2 threshold on the max-population-AF basis.

PM6 Not assessed: no parental testing or proband data were available to support an assumed de novo origin.

PP1 Not assessed: no affected relatives were tested, so no co-segregation evidence was available.

PP3 Not met: SpliceAI max delta 0.015 is far below the 0.2 splice-alteration cutoff, and missense predictors do not apply.

PP4 Not assessed: no proband phenotype or family-history data were available.

PP5 Not met: ClinVar VCV000726954 contains no expert-panel pathogenic classification (0 of 4 submissions).

Benign

BA1 Not met: highest subpopulation allele frequency 0.709% (gnomAD v4.1 EAS) falls below the >1% BA1 threshold.

BS3 Not assessed: no well-established functional study of this synonymous variant was available.

BS4 Not assessed: no family testing data existed to document absence of segregation.

BP2 Not assessed: no proband or family phase data (cis/trans with a pathogenic variant) were available.

BP5 Not assessed: no proband data were available to identify an alternate molecular basis of disease.

BP6 Not met: all 4 ClinVar submissions are ordinary clinical laboratories, with no expert-panel benign classification.

N/A · 11 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BS2 · BP1 · BP3 · BP4

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000284975; MAF= 0.02850%, 460/1614176 alleles, homozygotes = 2) and has highest observed frequency in the East Asian population (AF= 0.00708714; MAF= 0.70871%, 318/44870 alleles, homozygotes = 2); grpmax FAF= 0.00644595.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000717867; MAF= 0.07179%, 203/282782 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00846948; MAF= 0.84695%, 169/19954 alleles, homozygotes = 0); grpmax FAF= 0.00759882.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.0014657980456026058, 27/18420 alleles, homozygotes = 1).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.028% · 460 / 1,614,176
2 hom · FAF 0.64%

East Asian 318 / 44,870	0.71% 2 hom
South Asian 81 / 91,088	0.089%
Remaining individuals 51 / 62,508	0.082%
Middle Eastern 1 / 6,062	0.016%
Admixed American 3 / 60,028	0.005%
African/African American 1 / 75,040	0.0013%
European (non-Finnish) 5 / 1,180,028	0.00042%

+ 3 not observed (European (Finnish), Amish, Ashkenazi Jewish)

gnomAD v2.1

0.072% · 203 / 282,782
0 hom · FAF 0.76%

East Asian 169 / 19,954	0.85%
South Asian 29 / 30,614	0.095%
Remaining individuals 2 / 7,220	0.028%
Admixed American 1 / 35,424	0.0028%
European (non-Finnish) 2 / 129,142	0.0015%

+ 3 not observed (African/African American, Ashkenazi Jewish, European (Finnish))

gnomAD Canada 🇨🇦

0.15% · 27 / 18,420
1 hom · FAF 0.99%

East Asian 20 / 1,338	1.5% 1 hom
Remaining individuals 6 / 1,138	0.53%
South Asian 1 / 1,362	0.073%

+ 6 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, European (Finnish), Middle Eastern, European (non-Finnish))

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (3 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 726954)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57251228, n = 2 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & References.

Rule & framework references · cited for criterion definitions, not variant evidence

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 PMIDs not cited in assessment

25730230 ↗ Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine. CLINVAR

22947299 ↗ Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening. CLINVAR

23037933 ↗ Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children. CLINVAR

23881473 ↗ Newborn screening: education, consent, and the residual blood spot. The position of the national society of genetic counselors. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

31022120 ↗ ACOG Committee Opinion No. 778 Summary: Newborn Screening and the Role of the Obstetrician-Gynecologist. CLINVAR