rs746693911

Variant names:

• chr5-177513020-T-G
• rs746693911
• NM_016222.4:c.1293A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_016222.4(DDX41):​c.1293A>C​(p.Thr431Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DDX41 NM_016222.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.19
• 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen, Ambry Genetics
• acromesomelic dysplasia

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-177513020-T-G is Benign according to our data. Variant chr5-177513020-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 210842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.19 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX41	NM_016222.4	MANE Select	c.1293A>C	p.Thr431Thr	synonymous	Exon 12 of 17	NP_057306.2
	DDX41	NM_001321732.2		c.915A>C	p.Thr305Thr	synonymous	Exon 11 of 16	NP_001308661.1
	DDX41	NM_001321830.2		c.915A>C	p.Thr305Thr	synonymous	Exon 12 of 17	NP_001308759.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX41	ENST00000330503.12	TSL:1 MANE Select	c.1293A>C	p.Thr431Thr	synonymous	Exon 12 of 17	ENSP00000330349.8
	DDX41	ENST00000507955.6	TSL:1	n.*501A>C		non_coding_transcript_exon	Exon 12 of 17	ENSP00000422753.2
	DDX41	ENST00000507955.6	TSL:1	n.*501A>C		3_prime_UTR	Exon 12 of 17	ENSP00000422753.2

Frequencies

GnomAD3 genomes AF: 0.0000529 AC: 8 AN: 151266 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000887

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0123 AC: 2818 AN: 228542 AF XY: 0.0121

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.00271

Gnomad ASJ exome AF: 0.00640

Gnomad EAS exome AF: 0.0108

Gnomad FIN exome AF: 0.0429

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.0118

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00135 AC: 1935 AN: 1436040 Hom.: 0 Cov.: 34 AF XY: 0.00156 AC XY: 1111 AN XY: 712510

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00146 AC: 48 AN: 32916

American (AMR) AF: 0.00338 AC: 145 AN: 42900

Ashkenazi Jewish (ASJ) AF: 0.00158 AC: 39 AN: 24656

East Asian (EAS) AF: 0.00439 AC: 169 AN: 38516

South Asian (SAS) AF: 0.00144 AC: 119 AN: 82358

European-Finnish (FIN) AF: 0.00466 AC: 229 AN: 49162

Middle Eastern (MID) AF: 0.00304 AC: 17 AN: 5588

European-Non Finnish (NFE) AF: 0.000987 AC: 1086 AN: 1100470

Other (OTH) AF: 0.00140 AC: 83 AN: 59474

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000529 AC: 8 AN: 151370 Hom.: 0 Cov.: 33 AF XY: 0.0000406 AC XY: 3 AN XY: 73906

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000242 AC: 1 AN: 41326

American (AMR) AF: 0.0000657 AC: 1 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0000887 AC: 6 AN: 67658

Other (OTH) AF: 0.00 AC: 0 AN: 2106

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00256 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.42
DANN	Benign	0.65
PhyloP100		-3.2
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: rs746693911; hg19: chr5-176940021;