chr5-177515944-T-TCATC

Position:

chr5-177515944-T-TCATC

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_016222.4(DDX41):c.418_419insGATG(p.Asp140GlyfsTer2) variant causes a stop gained, frameshift change. The variant allele was found at a frequency of 0.000201 in 1,613,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

DDX41
NM_016222.4 stop_gained, frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10O:2

Conservation

PhyloP100: 7.07

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 Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 5-177515944-T-TCATC is Pathogenic according to our data. Variant chr5-177515944-T-TCATC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 210843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DDX41	NM_016222.4 linkuse as main transcript	c.418_419insGATG	p.Asp140GlyfsTer2	stop_gained, frameshift_variant	5/17	ENST00000330503.12	NP_057306.2
DDX41	NM_001321732.2 linkuse as main transcript	c.40_41insGATG	p.Asp14GlyfsTer2	stop_gained, frameshift_variant	4/16		NP_001308661.1
DDX41	NM_001321830.2 linkuse as main transcript	c.40_41insGATG	p.Asp14GlyfsTer2	stop_gained, frameshift_variant	5/17		NP_001308759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX41	ENST00000330503.12 linkuse as main transcript	c.418_419insGATG	p.Asp140GlyfsTer2	stop_gained, frameshift_variant	5/17	1	NM_016222.4	ENSP00000330349	P1

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251444

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000215

AC:

314

AN:

1461874

Hom.:

Cov.:

AF XY:

0.000204

AC XY:

148

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000276

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000658

AC:

AN:

152018

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74208

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.0000869

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

DDX41-related hematologic malignancy predisposition syndrome

Pathogenic:6Other:2

risk factor, no assertion criteria provided	literature only	OMIM	Mar 16, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 24, 2018	The DDX41 c.415_418dupGATG p.(Asp140GlyfsTer2) causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been identified in individuals with a phenotype consistent with familial myeloproliferative/lymphoproliferative neoplasms (Polprasert et al. 2015; Lewinsohn et al. 2016). At least three individuals, ranging in age from 55 to 76 years, from these families also carried the variant but did not show signs of disease, though incomplete penetrance has been reported (Lewinsohn et al. 2016). The highest frequency of this allele in the Genome Aggregation Database is 0.000166 in the European (non-Finnish) population (version 2.1.1). Cheah et al. (2017) report that the c.415_418dupGATG variant is the most common DDX41 variant in Caucasian patients and suggest that it may be a founder variant in this population. Based on the available evidence, the c.415_418dupGATG p.(Asp140GlyfsTer2) variant is classified as likely pathogenic for susceptibility to multiple types of familial myeloproliferative/lymphoproliferative neoplasms. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 13, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2024	Variant summary: DDX41 c.415_418dupGATG (p.Asp140GlyfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.7e-05 in 251444 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DDX41 causing DDX41-Related Hematologic Malignancy Predisposition Syndrome, allowing no conclusion about variant significance. c.415_418dupGATG has been reported in the literature in individuals affected with DDX41-Related Hematologic Malignancy Predisposition Syndrome (examples: Lewinsohn_2016 and Dalle_2020). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 26712909, 31400013). ClinVar contains an entry for this variant (Variation ID: 210843). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	Common recurrent germline variant, esp in persons of European ancestry [Polprasert et al 2015, Cheah et al 2017, Quesada et al 2019, Bannon et al 2021] -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jun 08, 2022	The DDX41 c.415_418dup (p.Asp140GlyfsTer2) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense-mediated decay. This variant has been reported in individuals with a personal and/or family history of acute myeloid leukemia and/or myelodysplastic syndrome (PMID: 25920683, 30963592, 31400013, 31484648, 33585199). This variant has a maximum subpopulation frequency of 0.017% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic for familial myeloproliferative/lymphoproliferative neoplasms. -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	May 12, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Labs, University Health Network	Feb 17, 2022	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Asp140Glyfs*2) in the DDX41 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DDX41 are known to be pathogenic (PMID: 26712909, 27133828). This variant is present in population databases (rs762890562, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with acute myeloid leukemia or myelodysplastic syndrome (PMID: 25920683, 30963592). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 210843). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26944477, 29372845, 26940275, 25920683, 26712909, 30963592, 31484648, 31400013, 27819178, 28637623, 28955657, 29790872, 26917736, 33778416, 33850299, 33585199) -

DDX41-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 2024

The DDX41 c.415_418dupGATG variant is predicted to result in a frameshift and premature protein termination (p.Asp140Glyfs*2). This variant has been reported to be causative for myelodysplastic syndrome and acute myeloid leukemia (for example, see: Polprasert et al. 2015. PubMed ID: 25920683; Lewinsohn et al. 2016. PubMed ID: 26712909). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/210843/). Frameshift variants in DDX41 are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. -

Acute myeloid leukemia

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 01, 2021

DNA sequence analysis of the DDX41 gene demonstrated a four base pair deletion in exon 5, c.415_418dup. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon at position 2 in the new reading frame, p.Asp140Glyfs*2. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated DDX41 protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a frequency of 0.017% in the European (non-Finnish) subpopulation. This pathogenic sequence change is a well described, recurrent variant that has previously been described in multiple individuals with DDX41-related myeloid malignancies (PMID: 25920683, 31484648, 26712909, 31400013, 30963592). This pathogenic sequence change is the most likely cause of this patient's phenotype. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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