chr5-177515766-G-A
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_016222.4(DDX41):c.490C>T(p.Arg164Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000147 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_016222.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DDX41 | NM_016222.4 | c.490C>T | p.Arg164Trp | missense_variant | Exon 6 of 17 | ENST00000330503.12 | NP_057306.2 | |
DDX41 | NM_001321732.2 | c.112C>T | p.Arg38Trp | missense_variant | Exon 5 of 16 | NP_001308661.1 | ||
DDX41 | NM_001321830.2 | c.112C>T | p.Arg38Trp | missense_variant | Exon 6 of 17 | NP_001308759.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000124 AC: 31AN: 250410Hom.: 0 AF XY: 0.000111 AC XY: 15AN XY: 135486
GnomAD4 exome AF: 0.000146 AC: 213AN: 1461846Hom.: 0 Cov.: 32 AF XY: 0.000139 AC XY: 101AN XY: 727224
GnomAD4 genome AF: 0.000164 AC: 25AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17AN XY: 74324
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:2
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in unrelated individuals with lymphoma (Li et al., 2022); Published functional studies demonstrate that this variant does not impact nuclear localization (Lewinsohn et al., 2016); This variant is associated with the following publications: (PMID: 28547672, 26917736, 27819178, 27928732, 28637623, 26712909, 35781188, 35671390) -
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 164 of the DDX41 protein (p.Arg164Trp). This variant is present in population databases (rs142143752, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with lymphoma and/or multiple myeloma (PMID: 26712909, 35671390). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 224638). 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 disruptive. Studies have shown that this missense change does not significantly alter or has an unclear effect on DDX41 gene expression (PMID: 26712909). 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. -
DNA sequence analysis of the DDX41 gene demonstrated a sequence change, c.490C>T, in exon 6 that results in an amino acid change, p.Arg164Trp. This sequence change has been described in the gnomAD database with a frequency of 0.16% in Ashkenazi Jewish populations (dbSNP rs142143752). The p.Arg164Trp change has been identified segregating with lymphoid malignancies in five individuals from one family (PMID: 26712909). This variant has also been seen in a second family where it segregates with lymphoid malignancies (verbal communication). The p.Arg164Trp change affects a highly conserved amino acid residue located adjacent to the Q motif, a region involved in adenosine triphosphate binding and hydrolysis, and thought to be important for regulating DDX41 helicase activity. The majority of in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide results for the p.Arg164Trp substitution that suggest it be pathogenic. Functional studies demonstrate that the p.Arg164Trp change does not overtly affect protein translation or localization (PMID: 26712909); however, the impact on protein activity or binding ability has not been determined. These collective evidences indicate this this sequence change is likely pathogenic. -
DDX41-related hematologic malignancy predisposition syndrome Uncertain:1Other:1
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Inborn genetic diseases Uncertain:1
The p.R164W variant (also known as c.490C>T), located in coding exon 6 of the DDX41 gene, results from a C to T substitution at nucleotide position 490. The arginine at codon 164 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported as a presumed germline finding in numerous individuals with a suspected or confirmed myeloid neoplasm (Li P et al. Blood, 2022 Aug;140:716-755; Tierens A et al. Front Oncol, 2023 Jun;13:1153082; Cheloor Kovilakam S et al. Blood, 2023 Oct;142:1185-1192). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at