17-64504098-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_004396.5(DDX5):c.326T>C(p.Ile109Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DDX5 NM_004396.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.78

Genes affected

DDX5 (HGNC:2746): (DEAD-box helicase 5) This gene encodes a member of the DEAD box family of RNA helicases that are involved in a variety of cellular processes as a result of its role as an adaptor molecule, promoting interactions with a large number of other factors. This protein is involved in pathways that include the alteration of RNA structures, plays a role as a coregulator of transcription, a regulator of splicing, and in the processing of small noncoding RNAs. Members of this family contain nine conserved motifs, including the conserved Asp-Glu-Ala-Asp (DEAD) motif, important to ATP binding and hydrolysis as well as RNA binding and unwinding activities. Dysregulation of this gene may play a role in cancer development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DDX5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDX5	NM_004396.5	c.326T>C	p.Ile109Thr	missense_variant	4/13	ENST00000225792.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDX5	ENST00000225792.10	c.326T>C	p.Ile109Thr	missense_variant	4/13	1	NM_004396.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2023

The c.326T>C (p.I109T) alteration is located in exon 4 (coding exon 4) of the DDX5 gene. This alteration results from a T to C substitution at nucleotide position 326, causing the isoleucine (I) at amino acid position 109 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	30
Dann	Benign	0.91
DEOGEN2	Uncertain	0.63	D;T;T;T;T;T;.;.;.;T;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;.;D;.
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Pathogenic	3.4	M;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.7	D;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.015	D;D;.;.;T;.;.;.;.;D;.
Polyphen		0.81	P;.;.;.;.;.;.;.;.;.;.
Vest4		0.83
MutPred		0.77		Gain of glycosylation at I109 (P = 0.0539);Gain of glycosylation at I109 (P = 0.0539);Gain of glycosylation at I109 (P = 0.0539);.;.;.;.;.;.;Gain of glycosylation at I109 (P = 0.0539);.;
MVP		0.94
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.81

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-62500216;