rs141601766

chr5-177516943-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 18P and 4B. PVS1 PS1_Moderate PP5_Very_Strong BS2

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:10 U:1 O:2
• Conservation: PhyloP100: 3.79

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_016222.4 (DDX41) was described as [Pathogenic] in ClinVar as 1707083
• PP5: Variant 5-177516943-C-T is Pathogenic according to our data. Variant chr5-177516943-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDX41	NM_016222.4	c.3G>A	p.Met1?	start_lost	1/17	ENST00000330503.12
DDX41	NM_001321732.2	c.-653G>A		5_prime_UTR_variant	1/16
DDX41	NM_001321830.2	c.-445G>A		5_prime_UTR_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDX41	ENST00000330503.12	c.3G>A	p.Met1?	start_lost	1/17	1	NM_016222.4	P1

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

GnomAD3 exomes AF: 0.0000815 AC: 20 AN: 245476 Hom.: 0 AF XY: 0.0000825 AC XY: 11 AN XY: 133370

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 SAS 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

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000573

Gnomad4 NFE exome AF: 0.000226

Gnomad4 OTH exome AF: 0.0000497

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

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000220 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:10 Uncertain:1 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DDX41-related hematologic malignancy predisposition syndrome Pathogenic:4 Uncertain:1 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 15, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 19, 2020	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 02, 2020	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. -
risk factor, no assertion criteria provided	literature only	OMIM	Mar 16, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 18, 2021	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. -
not provided, no classification provided	literature only	GeneReviews	-	Common recurrent germline variant, esp in persons of European ancestry [Cheah et al 2017, Quesada et al 2019, Bannon et al 2021] -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genomics Labs, University Health Network	Jul 23, 2018	- -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 01, 2024	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 protein 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. -

Bone marrow hypocellularity Pathogenic:1

Pathogenic, no assertion criteria provided

research

Bone Marrow Failure laboratory, Queen Mary University London

Aug 28, 2020

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 -

Myelodysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

research

Bone Marrow Failure laboratory, Queen Mary University London

Aug 28, 2020

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

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2023

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
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-0.65	N;.;.
REVEL	Benign	0.17
Sift	Uncertain	0.027	D;.;.
Sift4G	Benign	0.25	T;D;D
Polyphen		0.27	B;.;.
Vest4		0.84
MutPred		0.99		Gain of glycosylation at S4 (P = 0.0626);Gain of glycosylation at S4 (P = 0.0626);Gain of glycosylation at S4 (P = 0.0626);
MVP		0.60
ClinPred		0.70	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.64

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: rs141601766; hg19: chr5-176943944;