rs192297583

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

2
Splicing: ADA: 0.0004805
1

Clinical Significance

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

Conservation

PhyloP100: 0.633
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]

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 id 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 FAILED quality control check.
BS2
High AC in GnomAd4 at 229 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DDX41NM_016222.4 linkc.139-4T>G splice_region_variant, intron_variant Intron 2 of 16 ENST00000330503.12 NP_057306.2
DDX41NM_001321732.2 linkc.-244T>G 5_prime_UTR_variant Exon 2 of 16 NP_001308661.1
DDX41NM_001321830.2 linkc.-244T>G 5_prime_UTR_variant Exon 3 of 17 NP_001308759.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DDX41ENST00000330503.12 linkc.139-4T>G splice_region_variant, intron_variant Intron 2 of 16 1 NM_016222.4 ENSP00000330349.8 Q9UJV9

Frequencies

GnomAD3 genomes
AF:
0.00151
AC:
230
AN:
152168
Hom.:
0
Cov.:
32
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.:
23
Cov.:
32
AF XY:
0.00217
AC XY:
1580
AN XY:
726788
show subpopulations
Gnomad4 AFR exome
AF:
0.000269
AC:
9
AN:
33476
Gnomad4 AMR exome
AF:
0.00197
AC:
88
AN:
44720
Gnomad4 ASJ exome
AF:
0.0137
AC:
359
AN:
26136
Gnomad4 EAS exome
AF:
0.0000504
AC:
2
AN:
39700
Gnomad4 SAS exome
AF:
0.0101
AC:
871
AN:
86258
Gnomad4 FIN exome
AF:
0.0000380
AC:
2
AN:
52588
Gnomad4 NFE exome
AF:
0.00104
AC:
1152
AN:
1111994
Gnomad4 Remaining exome
AF:
0.00293
AC:
177
AN:
60376
Heterozygous variant carriers
0
172
344
516
688
860
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
48
96
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.:
0
Cov.:
32
AF XY:
0.00183
AC XY:
136
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.000241
AC:
0.000240581
AN:
0.000240581
Gnomad4 AMR
AF:
0.00183
AC:
0.00182983
AN:
0.00182983
Gnomad4 ASJ
AF:
0.0124
AC:
0.0123919
AN:
0.0123919
Gnomad4 EAS
AF:
0.000193
AC:
0.000192901
AN:
0.000192901
Gnomad4 SAS
AF:
0.00745
AC:
0.00745033
AN:
0.00745033
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.00156
AC:
0.00155892
AN:
0.00155892
Gnomad4 OTH
AF:
0.00142
AC:
0.00142045
AN:
0.00142045
Heterozygous variant carriers
0
10
20
30
40
50
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Variant carriers
0
10
20
30
40
50
<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.:
1
Bravo
AF:
0.00139
Asia WGS
AF:
0.00202
AC:
7
AN:
3478
EpiCase
AF:
0.00158
EpiControl
AF:
0.00249

ClinVar

Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Dec 11, 2017
Genetic Services Laboratory, University of Chicago
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Inborn genetic diseases Benign:1
Mar 20, 2024
Ambry Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as 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. -

not provided Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

DDX41-related disorder Benign:1
Feb 02, 2022
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as 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
-0.75
CADD
Benign
7.2
DANN
Benign
0.74
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Mutation Taster
=69/31
polymorphism

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs192297583; hg19: chr5-176943452; COSMIC: COSV109428891; COSMIC: COSV109428891; API