5-177513766-GC-AT

Variant names:

• chr5-177513766-GC-AT
• NM_016222.4:c.1016_1017delGCinsAT
• DDX41 p.Arg339His

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM5 PP2

The NM_016222.4(DDX41):​c.1016_1017delGCinsAT​(p.Arg339His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R339C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DDX41 NM_016222.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.04
• 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), ClinGen, G2P, Genomics England PanelApp, Ambry Genetics
• acromesomelic dysplasia

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_016222.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-177513768-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2136166.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.2847 (below the threshold of 3.09). Trascript score misZ: 3.1411 (above the threshold of 3.09). GenCC associations: The gene is linked to DDX41-related hematologic malignancy predisposition syndrome, acromesomelic dysplasia.

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.1016_1017delGCinsAT	p.Arg339His	missense	N/A	NP_057306.2
	DDX41	NM_001321732.2		c.638_639delGCinsAT	p.Arg213His	missense	N/A	NP_001308661.1	B3KRK2
	DDX41	NM_001321830.2		c.638_639delGCinsAT	p.Arg213His	missense	N/A	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.1016_1017delGCinsAT	p.Arg339His	missense	N/A	ENSP00000330349.8	Q9UJV9
	DDX41	ENST00000507955.6	TSL:1	n.*224_*225delGCinsAT		non_coding_transcript_exon	Exon 10 of 17	ENSP00000422753.2	A0A499FJW5
	DDX41	ENST00000507955.6	TSL:1	n.*224_*225delGCinsAT		3_prime_UTR	Exon 10 of 17	ENSP00000422753.2	A0A499FJW5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr5-176940767;