rs78923296

Variant names:

• chr5-177511717-G-A
• rs78923296
• NM_016222.4:c.*74C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016222.4(DDX41):​c.*74C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000941 in 1,586,982 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (11 hom.)
• Consequence: DDX41 NM_016222.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.213
• Publications: 0 publications found

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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, ClinGen
• acromesomelic dysplasia

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 5-177511717-G-A is Benign according to our data. Variant chr5-177511717-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 434911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00452 (688/152344) while in subpopulation AFR AF = 0.0158 (658/41574). AF 95% confidence interval is 0.0148. There are 2 homozygotes in GnomAd4. There are 337 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX41	NM_016222.4	MANE Select	c.*74C>T		3_prime_UTR	Exon 17 of 17	NP_057306.2
	DDX41	NM_001321732.2		c.*74C>T		3_prime_UTR	Exon 16 of 16	NP_001308661.1	B3KRK2
	DDX41	NM_001321830.2		c.*74C>T		3_prime_UTR	Exon 17 of 17	NP_001308759.1	B3KRK2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX41	ENST00000330503.12	TSL:1 MANE Select	c.*74C>T		3_prime_UTR	Exon 17 of 17	ENSP00000330349.8	Q9UJV9
	DDX41	ENST00000507955.6	TSL:1	n.*1151C>T		non_coding_transcript_exon	Exon 17 of 17	ENSP00000422753.2	A0A499FJW5
	DDX41	ENST00000507955.6	TSL:1	n.*1151C>T		3_prime_UTR	Exon 17 of 17	ENSP00000422753.2	A0A499FJW5

Frequencies

GnomAD3 genomes AF: 0.00453 AC: 689 AN: 152226 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.000561 AC: 805 AN: 1434638 Hom.: 11 Cov.: 31 AF XY: 0.000470 AC XY: 334 AN XY: 710552

African (AFR) AF: 0.0199 AC: 659 AN: 33068

American (AMR) AF: 0.00100 AC: 44 AN: 43910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24916

East Asian (EAS) AF: 0.00 AC: 0 AN: 39284

South Asian (SAS) AF: 0.0000715 AC: 6 AN: 83906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52260

Middle Eastern (MID) AF: 0.000530 AC: 3 AN: 5658

European-Non Finnish (NFE) AF: 0.0000156 AC: 17 AN: 1092458

Other (OTH) AF: 0.00128 AC: 76 AN: 59178

GnomAD4 genome AF: 0.00452 AC: 688 AN: 152344 Hom.: 2 Cov.: 33 AF XY: 0.00452 AC XY: 337 AN XY: 74500

African (AFR) AF: 0.0158 AC: 658 AN: 41574

American (AMR) AF: 0.00131 AC: 20 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00198 Hom.: 1

Bravo AF: 0.00491

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.0
DANN	Benign	0.66
PhyloP100		0.21
PromoterAI		0.0072	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs78923296; hg19: chr5-176938718;