5-177516720-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PP3_StrongBP6BS1

The NM_016222.4(DDX41):c.138+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000427 in 1,592,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

DDX41
NM_016222.4 splice_region, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 3.22

Publications

1 publications found

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 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

DDX41 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

BP6

Variant 5-177516720-C-T is Benign according to our data. Variant chr5-177516720-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1336382.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00023 (35/152386) while in subpopulation AFR AF = 0.000769 (32/41594). AF 95% confidence interval is 0.000559. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
DDX41	NM_016222.4 link	c.138+5G>A	splice_region_variant, intron_variant	Intron 2 of 16	ENST00000330503.12	NP_057306.2
DDX41	NM_001321732.2 link	c.-513G>A	5_prime_UTR_variant	Exon 2 of 16		NP_001308661.1
DDX41	NM_001321830.2 link	c.-310+5G>A	splice_region_variant, intron_variant	Intron 2 of 16		NP_001308759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX41	ENST00000330503.12 link	c.138+5G>A		splice_region_variant, intron_variant	Intron 2 of 16	1	NM_016222.4	ENSP00000330349.8

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000846

AC:

AN:

212810

AF XY:

0.0000430

show subpopulations

Gnomad AFR exome

AF:

0.000731

Gnomad AMR exome

AF:

0.000286

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000229

AC:

AN:

1439722

Hom.:

Cov.:

AF XY:

0.00000979

AC XY:

AN XY:

714694

show subpopulations

African (AFR)

AF:

0.000699

AC:

AN:

32908

American (AMR)

AF:

0.000214

AC:

AN:

42076

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25724

East Asian (EAS)

AF:

0.00

AC:

AN:

38356

South Asian (SAS)

AF:

0.00

AC:

AN:

83802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50222

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5434

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101730

Other (OTH)

AF:

0.0000168

AC:

AN:

59470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000230

AC:

AN:

152386

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74518

show subpopulations

African (AFR)

AF:

0.000769

AC:

AN:

41594

American (AMR)

AF:

0.000131

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000394

Hom.:

Bravo

AF:

0.000246

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

DDX41-related hematologic malignancy predisposition syndrome

Uncertain:2

Mar 22, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 06, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1Benign:1

Jul 08, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this variant does not alter splicing; Reported as a germline variant and co-observed with a DDX41 frameshift variant in a patient with myeloproliferative neoplasm and essential thrombocythemia (Li et al., 2022); This variant is associated with the following publications: (PMID: 35671390)

Jun 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Uncertain:1

Aug 27, 2021

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This change does not appear to have been previously described in patients with DDX41-related disorders. This sequence change has been described in the gnomAD with a population frequency of 0.086% in the African subpopulation (dbSNP rs187714514). Based on in silico splice prediction programs, this sequence change may impact normal splicing of the DDX41 gene, which may result in an abnormal protein, however functional studies have not been performed to prove this conclusively. The functional significance of this sequence change is not known at present and its contribution to this patient's disease phenotype cannot definitively be determined.

Inborn genetic diseases

Benign:1

Mar 20, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

DDX41-related disorder

Benign:1

Feb 17, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

3.2

PromoterAI

-0.063

Neutral

(source)

Mutation Taster

=16/84

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.21

Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over