rs142143752

chr5-177515766-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate 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:1 U:3 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

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DDX41
• BP4: Computational evidence support a benign effect (MetaRNN=0.22977674).
• BS2: High AC in GnomAd at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDX41	NM_016222.4	c.490C>T	p.Arg164Trp	missense_variant	6/17	ENST00000330503.12
DDX41	NM_001321732.2	c.112C>T	p.Arg38Trp	missense_variant	5/16
DDX41	NM_001321830.2	c.112C>T	p.Arg38Trp	missense_variant	6/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDX41	ENST00000330503.12	c.490C>T	p.Arg164Trp	missense_variant	6/17	1	NM_016222.4	P1

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

GnomAD3 exomes AF: 0.000124 AC: 31 AN: 250410 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135486

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 SAS 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

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000140

Gnomad4 OTH exome AF: 0.000215

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

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000207 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:1 Uncertain:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 29, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2022	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 Uncertain:1 Other:1

risk factor, no assertion criteria provided	literature only	OMIM	Mar 16, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -

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
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	1.0	D
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

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;