rs747072227
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PP2PP3_ModeratePP5_Very_Strong
The NM_016222.4(DDX41):c.1187T>C(p.Ile396Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )
Consequence
DDX41
NM_016222.4 missense
NM_016222.4 missense
Scores
7
6
3
Clinical Significance
Conservation
PhyloP100: 9.05
Genes affected
DDX41 (HGNC:18674): (DEAD-box helicase 41) DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure, such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of the DEAD box protein family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. The protein encoded by this gene is a member of the DEAD box protein family and interacts with several spliceosomal proteins. In addition, the encoded protein may recognize the bacterial second messengers cyclic di-GMP and cyclic di-AMP, resulting in the induction of genes involved in the innate immune response. [provided by RefSeq, Jan 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM1
?
In a domain Helicase ATP-binding (size 184) in uniprot entity DDX41_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_016222.4
PP2
?
Missense variant where missense usually causes diseases, DDX41
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.901
PP5
?
Variant 5-177513396-A-G is Pathogenic according to our data. Variant chr5-177513396-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DDX41 | NM_016222.4 | c.1187T>C | p.Ile396Thr | missense_variant | 11/17 | ENST00000330503.12 | |
DDX41 | NM_001321732.2 | c.809T>C | p.Ile270Thr | missense_variant | 10/16 | ||
DDX41 | NM_001321830.2 | c.809T>C | p.Ile270Thr | missense_variant | 11/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DDX41 | ENST00000330503.12 | c.1187T>C | p.Ile396Thr | missense_variant | 11/17 | 1 | NM_016222.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152140Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251314Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135840
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GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461834Hom.: 0 Cov.: 37 AF XY: 0.0000316 AC XY: 23AN XY: 727228
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 15, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27721487, 27928732, 33692849, 36455200, 35781188, 33585199, 36322930, 36112138, 25920683) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 25, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 396 of the DDX41 protein (p.Ile396Thr). This variant is present in population databases (rs747072227, gnomAD 0.007%). This missense change has been observed in individuals with leukemia and/or myelodysplastic syndrome (PMID: 25920683, 33585199, 36322930; Invitae). ClinVar contains an entry for this variant (Variation ID: 224635). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 05, 2021 | DNA sequence analysis of the DDX41 gene demonstrated a sequence change, c.1187T>C, in exon 11 that results in an amino acid change, p.Ile396Thr. This sequence change has been described in the gnomAD database with frequency of 0.006% in the African American/African subpopulation (dbSNP rs747072227). The p.Ile396Thr change affects a moderately conserved amino acid residue located in the DEAD domain of the DDX41 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ile396Thr substitution. This sequence change has been described in identical twin brothers with a personal history of myelodysplastic syndrome (MDS) and family history of acute myeloid leukemia along with a recurrent somatic mutation in DDX41 (PMID: 25920683) and in a woman with MDS and history of ovarian cancer (PMID: 33585199). Collectively, these evidences indicate that this sequence change is likely pathogenic, however functional studies have not been performed to prove this conclusively. - |
DDX41-related hematologic malignancy predisposition syndrome Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Mar 16, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
0.47
.;P
Vest4
0.97
MutPred
0.79
.;Loss of stability (P = 0.0034);
MVP
MPC
1.4
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at