rs141601766

Variant names:

• chr5-177516943-C-T
• rs141601766
• NM_016222.4:c.3G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PS1_Moderate PP5_Very_Strong

The NM_016222.4(DDX41):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000174 in 1,612,668 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: DDX41 NM_016222.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 U:1 O:2
• Conservation: PhyloP100: 3.79
• Publications: 29 publications found

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 Gene-Disease associations (from GenCC):

• DDX41-related hematologic malignancy predisposition syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen, Ambry Genetics
• acromesomelic dysplasia

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 27 pathogenic variants. Next in-frame start position is after 127 codons. Genomic position: 177515984. Lost 0.203 part of the original CDS.
• PS1: Another start lost variant in NM_016222.4 (DDX41) was described as [Pathogenic] in ClinVar
• PP5: Variant 5-177516943-C-T is Pathogenic according to our data. Variant chr5-177516943-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 224637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDX41	NM_016222.4	c.3G>A	p.Met1?	start_lost	Exon 1 of 17	ENST00000330503.12	NP_057306.2
DDX41	NM_001321732.2	c.-653G>A		5_prime_UTR_variant	Exon 1 of 16		NP_001308661.1
DDX41	NM_001321830.2	c.-445G>A		5_prime_UTR_variant	Exon 1 of 17		NP_001308759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX41	ENST00000330503.12	c.3G>A	p.Met1?	start_lost	Exon 1 of 17	1	NM_016222.4	ENSP00000330349.8

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152256 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000815 AC: 20 AN: 245476 AF XY: 0.0000825

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000156

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000179 AC: 261 AN: 1460294 Hom.: 0 Cov.: 31 AF XY: 0.000173 AC XY: 126 AN XY: 726318

African (AFR) AF: 0.0000598 AC: 2 AN: 33468

American (AMR) AF: 0.0000224 AC: 1 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.0000573 AC: 3 AN: 52374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000226 AC: 251 AN: 1111584

Other (OTH) AF: 0.0000497 AC: 3 AN: 60366

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152374 Hom.: 0 Cov.: 32 AF XY: 0.0000805 AC XY: 6 AN XY: 74514

African (AFR) AF: 0.0000481 AC: 2 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68042

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000205 Hom.: 0

Bravo AF: 0.000117

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000495 AC: 6

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16 Uncertain:1 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DDX41-related hematologic malignancy predisposition syndrome Pathogenic:8 Uncertain:1 Other:2

Nov 18, 2021

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DDX41 c.3G>A (p.Met1Ile) variant is predicted to disrupt the initiator codon and thus potentially may interfere with protein expression. Across a selection of the available literature, the p.Met1Ile variant has been identified in at least 16 individuals with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) and was shown to segregate in at least one family (Lewinsohn et al. 2016; Sébert et al. 2019; Quesada et al. 2019; Rio-Machin et al. 2020). Control data are unavailable for this variant, which is reported at a frequency of 0.000153 in the European (non-Finnish) population of the Genome Aggregation Database version 2.1.1 and is found in a region of good sequence coverage. A second initiation codon variant is reported at the Met1 residue in a proband with AML (Sébert et al. 2019). Expression studies in HEK cells illustrate the p.Met1Ile variant exhibits altered cellular localization when compared to wildtype DDX41 (Lewinsohn et al. 2016). Based on the evidence, the p.Met1Ile variant is classified as pathogenic for DDX41-related hematologic malignancy predisposition syndrome.

Mar 16, 2023

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Nov 17, 2023

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DDX41 c.3G>A; p.Met1? variant (rs141601766), is reported in the literature in several individuals and families with predisposition to myeloid neoplasms, especially myelodysplastic syndrome and acute myeloid leukemia (Berger 2017, Cardoso 2016, Jelloul 2023, Lewinsohn 2016, Li 2022, Quesada 2019, Rio-Machin 2020, Sebert 2019). Functional analyses of the variant protein demonstrate reduced protein size, supporting altered translation and subcellular localization (Lewinsohn 2016). This variant is also reported in ClinVar (Variation ID: 224637). This variant is found in the general population with an overall allele frequency of 0.008% (23/276,878 alleles) in the Genome Aggregation Database (v2.1.1). This variant abolishes the canonical translation initiation site, which is likely to disrupt gene function. Based on available information, this variant is considered to be pathogenic. References: Berger G et al. Re-emergence of acute myeloid leukemia in donor cells following allogeneic transplantation in a family with a germline DDX41 mutation. Leukemia. 2017 Feb. PMID: 27795557. Cardoso SR et al. Germline heterozygous DDX41 variants in a subset of familial myelodysplasia and acute myeloid leukemia. Leukemia. 2016 Oct. PMID: 27133828. Jelloul FZ et al. DDX41 mutations in patients with non-myeloid hematologic neoplasms. Am J Hematol. 2023 May 8. PMID: 37154083. Lewinsohn M et al. Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies. Blood. 2016 Feb 25. PMID: 26712909. Li P et al. The genetic landscape of germline DDX41 variants predisposing to myeloid neoplasms. Blood. 2022 Jun 7. PMID: 35671390. Quesada AE et al. DDX41 mutations in myeloid neoplasms are associated with male gender, TP53 mutations and high-risk disease. Am J Hematol. 2019 Apr 8. PMID: 30963592 Rio-Machin A et al. The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants. Nat Commun. 2020 Feb 25. PMID: 32098966 Sebert M et al. Germline DDX41 mutations define a significant entity within adult MDS/AML patients. Blood. 2019 Oct 24. PMID: 31484648

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Common recurrent germline variant, esp in persons of European ancestry [Cheah et al 2017, Quesada et al 2019, Bannon et al 2021]

Jul 23, 2018

Clinical Genomics Labs, University Health Network

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 02, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DDX41 c.3G>A has been reported in multiple families segregating myeloproliferative and lymphoproliferative neoplasms. This DDX41 variant (rs141601766) is rare (<0.1%) in a large population dataset (gnomAD: 23/276878 total alleles; 0.0083%; no homozygotes) and it has been reported in ClinVar. Functional studies of p.Met1Ile indicate that an alternate, downstream methioinine is used for initiation of translation and that the resulting protein is mislocalized because it lacks a nuclear locationization signal. We consider this variant to be pathogenic.

Oct 04, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 19, 2020

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the DDX41 gene demonstrated a sequence change, c.3G>A, in exon 1 that affects the transcription start codon, p.Met1?. This pathogenic sequence change has previously been described in patients and families with DDX41-related hereditary myelodysplastic syndrome (MDS) and AML (PMIDs: 26712909, 27133828, 27795557). Studies have shown that the disruption of the initiating methionine resulted in a predominant smaller protein (PMID: 26712909).

May 13, 2025

Saint-Louis Hospital, Assistance Publique Hôpitaux de Paris

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant DDX41(NM_016222.4):c.3G>A:p.(Met1?) is suspected to induce start loss of the transcription. Loss-of-function variants in DDX41 are known to be pathogenic (PMID: 26712909, 27133828). It has been reported in individuals with suspected or confirmed predisposition to myeloid malignancies (Quesada et al.2019, PMID: 30963592; Lewinsohn et al, 2016, PMID: 26712909; Sébert et al, 2019, PMID: 31484648; Rio-Machin et al, 2020, PMID:32098966 ).

not provided Pathogenic:4

Mar 03, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Confirmed or presumably germline variant in individuals with DDX41-related phenotypes referred for genetic testing at GeneDx and in published literature (Quesada et al., 2019; Sbert et al., 2019; Rio-Machin et al., 2020; Bannon et al., 2021); Published functional studies suggest a damaging effect: shortened protein product that demonstrated altered cellular localization (Lewinsohn et al., 2016); This variant is associated with the following publications: (PMID: 26712909, 27795557, 27210295, 27133828, 31484648, 30963592, 32098966, 33585199, 28104920, 34671111, 33615436, 33692849)

Nov 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the DDX41 mRNA. The next in-frame methionine is located at codon 127. This variant is present in population databases (rs141601766, gnomAD 0.01%). Disruption of the initiator codon has been observed in individual(s) with acute myeloid leukemia, myelodysplastic syndrome and chronic myeloid leukemia (PMID: 26712909, 27133828, 27795557). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 224637). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects DDX41 function (PMID: 26712909). For these reasons, this variant has been classified as Pathogenic.

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Bone marrow hypocellularity Pathogenic:1

Aug 28, 2020

Bone Marrow Failure laboratory, Queen Mary University London

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

This heterozygous start-loss variant of DDX41 was identified in a 20-year old male with pancytopenia. The following ACMG/AMP criteria were used: PVS1, PS1, PM4, PP3

Inborn genetic diseases Pathogenic:1

Sep 12, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? pathogenic mutation (also known as c.3G>A) is located in coding exon 1 of the DDX41 gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). This variant has been reported in several individual(s) with DDX41-related hematologic malignancy predisposition syndrome (Cheloor Kovilakam S. et al, Blood 2023 Oct;142(14):1185-1192; Lewinsohn M. et al, Blood 2016 Feb;127(8):1017-23; Alkhateeb HB. et al, Blood Adv 2022 Jan;6(2):528-532; Li P. et al, Blood 2022 Aug;140(7):716-755; Jelloul FZ. et al, Am J Hematol 2023 Aug;98(8):E193-E196; Nanaa A. et al, Br J Haematol 2024 Jan;204(1):171-176). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

Myelodysplasia Pathogenic:1

Aug 28, 2020

Bone Marrow Failure laboratory, Queen Mary University London

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

This heterozygous start-loss variant of DDX41 was identified in a 41-year old female with MDS. She had inherited this variant from her father. The following ACMG/AMP criteria were used: PVS1, PS1, PM4, PP3

DDX41-related disorder Pathogenic:1

Jul 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DDX41 c.3G>A variant is predicted to disrupt the translation initiation site (Start loss). This variant was found in several families with a history of hematologic malignancies (see, for example, Lewinsohn et al. 2016. PubMed ID: 26712909; Cardoso et al. 2016. PubMed ID: 27133828; Quesada et al. 2019. PubMed ID: 30963592). The c.3G>A variant was reported primarily in patients with late onset MDS/AML, but it was also reported in at least one patient with chronic myeloid leukemia and one patient with AML and non-Hodgkin lymphoma. Biochemical studies indicate the c.3G>A substitution results in altered translation of a smaller DDX41 protein with improper cellular localization (Lewinsohn et al. 2016. PubMed ID: 26712909). This variant is reported in 0.015% of alleles in individuals of European (non-Finnish) descent in gnomAD and is interpreted as likely pathogenic or pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/224637/). This variant is interpreted as pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T;T;.
Eigen	Benign	0.060
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	.;.;.
PhyloP100		3.8
PROVEAN	Benign	-0.65	N;.;.
REVEL	Benign	0.17
Sift	Uncertain	0.027	D;.;.
Sift4G	Benign	0.25	T;D;D
Vest4		0.84
ClinPred		0.70	D
GERP RS		4.4
PromoterAI		-0.095	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.64
Mutation Taster		=4/196	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs141601766; hg19: chr5-176943944;