chr5-177512369-C-T

Position:

• chr5-177512369-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_016222.4(DDX41):​c.1574G>A​(p.Arg525His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DDX41 NM_016222.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2 O:2
• Conservation: PhyloP100: 7.81

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDX41	NM_016222.4	c.1574G>A	p.Arg525His	missense_variant	15/17	ENST00000330503.12	NP_057306.2
DDX41	NM_001321732.2	c.1196G>A	p.Arg399His	missense_variant	14/16		NP_001308661.1
DDX41	NM_001321830.2	c.1196G>A	p.Arg399His	missense_variant	15/17		NP_001308759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX41	ENST00000330503.12	c.1574G>A	p.Arg525His	missense_variant	15/17	1	NM_016222.4	ENSP00000330349.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 59

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

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

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Labs, University Health Network	Feb 17, 2022	- -
risk factor, no assertion criteria provided	literature only	OMIM	Mar 16, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	Most common somatic variant; also reported in the germline [Kadono et al 2016, Lewinsohn et al 2016, Cheah et al 2017] -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 28, 2022	Experimental studies have shown that this missense change affects DDX41 function (PMID: 25920683, 27174803). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 224634). This missense change has been observed in individual(s) with leukemia (PMID: 26712909). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 525 of the DDX41 protein (p.Arg525His). 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	May 12, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive, some suggesting that this variant by itself does not significantly affect protein translation or localization, some suggesting a possible hypomorphic effect, and some suggesting inhibition of proliferation and ATPase activity (Kadono et al., 2016; Lewinsohn et al., 2016; Chlon et al., 2021); Observed in the germline of an individual with myelodysplastic syndrome in published literature (Lewinsohn et al., 2016); Common second hit somatic variant observed in many affected individuals who also have a DDX41 germline variant (Polprasert et al., 2015); This variant is associated with the following publications: (PMID: 26712909, 34473945, 31713024, 34349893, 27174803, 33929502, 33836623, 33585199, 33692849, 27721487, 25920683) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	.;D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	.;H
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.99
MutPred		0.81		.;Loss of methylation at R525 (P = 0.0123);
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.0
Varity_R		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs869312828; hg19: chr5-176939370; COSMIC: COSV57252452; COSMIC: COSV57252452;