rs142143752

Variant names:

• chr5-177515766-G-A
• rs142143752
• NM_016222.4:c.490C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP2 PP5 BP4 BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R164Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: DDX41 NM_016222.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4 O:1
• Conservation: PhyloP100: 3.25

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]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.2847 (below the threshold of 3.09). Trascript score misZ: 3.1411 (above the threshold of 3.09). GenCC associations: The gene is linked to DDX41-related hematologic malignancy predisposition syndrome.
• PP5: Variant 5-177515766-G-A is Pathogenic according to our data. Variant chr5-177515766-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224638.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=2}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22977674). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd4 at 25 AD gene.

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

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX41	ENST00000330503.12	c.490C>T	p.Arg164Trp	missense_variant	Exon 6 of 17	1	NM_016222.4	ENSP00000330349.8

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000124 AC: 31 AN: 250410 AF XY: 0.000111

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000621

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000146 AC: 213 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.000139 AC XY: 101 AN XY: 727224

Gnomad4 AFR exome AF: 0.0000597 AC: 2 AN: 33480

Gnomad4 AMR exome AF: 0.0000671 AC: 3 AN: 44724

Gnomad4 ASJ exome AF: 0.00138 AC: 36 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.0000116 AC: 1 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53378

Gnomad4 NFE exome AF: 0.000140 AC: 156 AN: 1112010

Gnomad4 Remaining exome AF: 0.000215 AC: 13 AN: 60392

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74324

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00202 AC: 0.00201729 AN: 0.00201729

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000235 AC: 0.00023519 AN: 0.00023519

Gnomad4 OTH AF: 0.000478 AC: 0.000478011 AN: 0.000478011

Alfa AF: 0.000205 Hom.: 0

Bravo AF: 0.000136

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 29, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 16, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

DDX41-related hematologic malignancy predisposition syndrome Pathogenic:1 Uncertain:1 Other:1

Oct 30, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 13, 2025

Saint-Louis Hospital, Assistance Publique Hôpitaux de Paris

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant DDX41 (NM_016222.4):c.490C>T:p.(Arg164Trp) is very rare in control population databases (<10-4) and predicted to be pathogenic according to several algorithms (Alphamisense score at 0.895). It has been reported in individuals with suspected or confirmed predisposition to myeloid malignancies (Li et al, Blood, 2022, PMID: 35671390 ; Tierens et al, 2023, PMID: 37434984; Cheloor Kovilakam et al, 2023, PMID: 37506341) -

Mar 16, 2023

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Uncertain:1

Dec 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	.;D;T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Pathogenic	3.1	.;M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.6	D;D;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.0090	D;D;.
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.98	.;D;.
Vest4		0.90, 0.99
MVP		0.69
MPC		0.97
ClinPred		0.40	T
GERP RS		1.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.56
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs142143752; hg19: chr5-176942767; COSMIC: COSV57903864; COSMIC: COSV57903864;