Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016222.4(DDX41):c.139-4T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,613,240 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 23 hom. )

Consequence

DDX41
NM_016222.4 splice_region, intron

Scores

Splicing: ADA: 0.0004805

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.633

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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 5-177516451-A-C is Benign according to our data. Variant chr5-177516451-A-C is described in ClinVar as Benign. ClinVar VariationId is 434915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0015 (229/152286) while in subpopulation SAS AF = 0.00745 (36/4832). AF 95% confidence interval is 0.00553. There are 0 homozygotes in GnomAd4. There are 136 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 23 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016222.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
DDX41	NM_016222.4	MANE Select	c.139-4T>G	splice_region intron	N/A	NP_057306.2
DDX41	NM_001321732.2		c.-244T>G	5_prime_UTR	Exon 2 of 16	NP_001308661.1
DDX41	NM_001321830.2		c.-244T>G	5_prime_UTR	Exon 3 of 17	NP_001308759.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
DDX41	ENST00000330503.12	TSL:1 MANE Select	c.139-4T>G	splice_region intron	N/A	ENSP00000330349.8
DDX41	ENST00000507955.6	TSL:1	n.139-4T>G	splice_region intron	N/A	ENSP00000422753.2
DDX41	ENST00000515562.1	TSL:1	n.172-4T>G	splice_region intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00151

AC:

230

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00765

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00156

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00261

AC:

655

AN:

250718

AF XY:

0.00299

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.0126

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00142

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00186

AC:

2718

AN:

1460954

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

1580

AN XY:

726788

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33476

American (AMR)

AF:

0.00197

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0137

AC:

359

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0101

AC:

871

AN:

86258

European-Finnish (FIN)

AF:

0.0000380

AC:

AN:

52588

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00104

AC:

1152

AN:

1111994

Other (OTH)

AF:

0.00293

AC:

177

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

172

344

516

688

860

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.00150

AC:

229

AN:

152286

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

136

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41566

American (AMR)

AF:

0.00183

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00745

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00156

AC:

106

AN:

67996

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.00226

Hom.:

Bravo

AF:

0.00139

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00158

EpiControl

AF:

0.00249

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

DDX41-related disorder (1)

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

7.2

(source)

DANN

Benign

0.74

PhyloP100

0.63

PromoterAI

-0.024

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00048

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over