rs192297583

Positions:

chr5-177516451-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016222.4(DDX41):c.139-4T>G variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0004805

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]

DDX41 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 229 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE
DDX41	NM_016222.4 linkuse as main transcript	c.139-4T>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000330503.12
DDX41	NM_001321732.2 linkuse as main transcript	c.-244T>G	5_prime_UTR_variant	2/16
DDX41	NM_001321830.2 linkuse as main transcript	c.-244T>G	5_prime_UTR_variant	3/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDX41	ENST00000330503.12 linkuse as main transcript	c.139-4T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_016222.4	P1

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

GnomAD3 exomes

AF:

0.00261

AC:

655

AN:

250718

Hom.:

AF XY:

0.00299

AC XY:

405

AN XY:

135640

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 SAS exome

AF:

0.00898

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

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00197

Gnomad4 ASJ exome

AF:

0.0137

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0101

Gnomad4 FIN exome

AF:

0.0000380

Gnomad4 NFE exome

AF:

0.00104

Gnomad4 OTH exome

AF:

0.00293

GnomAD4 genome

AF:

0.00150

AC:

229

AN:

152286

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

136

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.0124

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00745

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00156

Gnomad4 OTH

AF:

0.00142

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

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 11, 2017

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2024

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

DDX41-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 02, 2022

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

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.

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