Starting

Initialising…

DDX41

Final classification

VUS

DDX41 c.1589G>A · p.Gly530Asp

DDX41

Gene

DDX41

Transcript

NM_016222.2

HGVS · transcript:coding

NM_016222.2:c.1589G>A

Consequence

N/A

GRCh38

chr5:177512354 C>T

GRCh37

chr5:176939355 C>T

Basis Generic ACMG/AMP final classification combination rules (PMID:25741868) were applied because the retrieved DDX41 ClinGen Myeloid Malignancy specification did not provide a complete usable final-classification rule set. ▾

Generic ACMG/AMP final classification combination rules (PMID:25741868) were applied because the retrieved DDX41 ClinGen Myeloid Malignancy specification did not provide a complete usable final-classification rule set.

Classification rationale

PM2PP3 VUS

DDX41 c.1589G>A

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.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in the general population.² 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 0.03.³

PM2 + PP3 → VUS

1 cosmicclinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 prefetchspliceai ↗

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

DDX41 NM_016222.2

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: DDX41, an RNA helicase involved in innate immunity, is recurrently altered by mutation in hematopoietic malignancies.

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; COSV57250947, n = 4 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

Hotspots ↗

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

Cancer hotspots