17-64502953-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.956T>C(p.Val319Ala) 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: 32)
• Consequence: DDX5 NM_004396.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.72

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, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDX5	NM_004396.5	c.956T>C	p.Val319Ala	missense_variant	8/13	ENST00000225792.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDX5	ENST00000225792.10	c.956T>C	p.Val319Ala	missense_variant	8/13	1	NM_004396.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Oct 05, 2022

The c.956T>C (p.V319A) alteration is located in exon 8 (coding exon 8) of the DDX5 gene. This alteration results from a T to C substitution at nucleotide position 956, causing the valine (V) at amino acid position 319 to be replaced by an alanine (A). 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	0.99
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	28
Dann	Benign	0.97
DEOGEN2	Uncertain	0.48	T;.;T;T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.7	H;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
REVEL	Pathogenic	0.91
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.98	D;.;.;.
Vest4		0.83
MutPred		0.52		Loss of stability (P = 0.0529);.;Loss of stability (P = 0.0529);.;
MVP		0.88
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.89

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: chr17-62499071;