rs187714514
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PP3_StrongBS2_Supporting
The NM_016222.4(DDX41):c.138+5G>T variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,591,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_016222.4 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DDX41 | NM_016222.4 | c.138+5G>T | splice_donor_5th_base_variant, intron_variant | ENST00000330503.12 | |||
DDX41 | NM_001321732.2 | c.-513G>T | 5_prime_UTR_variant | 2/16 | |||
DDX41 | NM_001321830.2 | c.-310+5G>T | splice_donor_5th_base_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DDX41 | ENST00000330503.12 | c.138+5G>T | splice_donor_5th_base_variant, intron_variant | 1 | NM_016222.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000788 AC: 12AN: 152268Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000136 AC: 29AN: 212810Hom.: 0 AF XY: 0.000129 AC XY: 15AN XY: 116404
GnomAD4 exome AF: 0.000138 AC: 199AN: 1439718Hom.: 0 Cov.: 31 AF XY: 0.000144 AC XY: 103AN XY: 714692
GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152268Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74390
ClinVar
Submissions by phenotype
DDX41-related hematologic malignancy predisposition syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Mar 03, 2022 | The DDX41 c.138+5G>T intronic change results from a G to T substitution at the +5 position of intron 2 of the DDX41 gene. Algorithms that predict the impact of sequence changes on splicing indicate that this change may result in loss of the native donor at c.138 (PP3), but internal RNA data demonstrates normal splicing (BS3_supporting). This variant has a maximum subpopulation frequency of 0.026% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/5-176943721-C-A). To our knowledge, this variant has not been reported in individuals with DDX41-related hematologic malignancy predisposition syndrome. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3, BS3_supporting. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 11, 2023 | In silico analysis supports that this variant does not alter splicing; Observed in individuals with hematologic malignancies (Li et al., 2022; Badar et al., 2023); This variant is associated with the following publications: (PMID: 35671390, 37199125) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 13, 2024 | This sequence change falls in intron 2 of the DDX41 gene. It does not directly change the encoded amino acid sequence of the DDX41 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs187714514, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with DDX41-related conditions (PMID: 35671390, 37199125). ClinVar contains an entry for this variant (Variation ID: 434923). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 26, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at