rs192297583

chr5-177516451-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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:3
• Conservation: PhyloP100: 0.633

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]

ACMG classification

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 GnomAd at 230 AD gene.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDX41	ENST00000330503.12	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.: 0 Cov.: 32

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.: 8 AF XY: 0.00299 AC XY: 405 AN XY: 135640

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.: 23 Cov.: 32 AF XY: 0.00217 AC XY: 1580 AN XY: 726788

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.: 0 Cov.: 32 AF XY: 0.00183 AC XY: 136 AN XY: 74470

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.: 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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 11, 2017

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

DDX41-related disorder Benign:1

Benign, criteria provided, single submitter

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

Other links and lift over

dbSNP: rs192297583; hg19: chr5-176943452;