rs142143752

Positions:

chr5-177515766-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_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

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

DDX41
NM_016222.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3O:1

Conservation

PhyloP100: 3.25

Variant links:

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]

DDX41 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DDX41. . Gene score misZ 2.2847 (greater than the threshold 3.09). Trascript score misZ 3.1411 (greater than threshold 3.09). GenCC has associacion of gene with DDX41-related hematologic malignancy predisposition syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.22977674).

BS2

High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DDX41	NM_016222.4 linkuse as main transcript	c.490C>T	p.Arg164Trp	missense_variant	6/17	ENST00000330503.12	NP_057306.2
DDX41	NM_001321732.2 linkuse as main transcript	c.112C>T	p.Arg38Trp	missense_variant	5/16		NP_001308661.1
DDX41	NM_001321830.2 linkuse as main transcript	c.112C>T	p.Arg38Trp	missense_variant	6/17		NP_001308759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX41	ENST00000330503.12 linkuse as main transcript	c.490C>T	p.Arg164Trp	missense_variant	6/17	1	NM_016222.4	ENSP00000330349	P1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

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:

AN:

250410

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

135486

show subpopulations

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.:

Cov.:

AF XY:

0.000139

AC XY:

101

AN XY:

727224

show subpopulations

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:

AN:

152174

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74324

show subpopulations

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.:

Bravo

AF:

0.000136

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
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	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:1Other: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

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

.;D;T

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.78

LIST_S2

Pathogenic

0.99

.;D;D

M_CAP

Benign

0.075

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Pathogenic

3.1

.;M;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.85

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over