17-64500311-C-T

Position:

• chr17-64500311-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_004396.5(DDX5):​c.1457G>A​(p.Arg486Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign 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: 6.04

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DDX5
• BP4: Computational evidence support a benign effect (MetaRNN=0.23442516).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDX5	NM_004396.5	c.1457G>A	p.Arg486Lys	missense_variant	13/13	ENST00000225792.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDX5	ENST00000225792.10	c.1457G>A	p.Arg486Lys	missense_variant	13/13	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

May 25, 2022

The c.1457G>A (p.R486K) alteration is located in exon 13 (coding exon 13) of the DDX5 gene. This alteration results from a G to A substitution at nucleotide position 1457, causing the arginine (R) at amino acid position 486 to be replaced by a lysine (K). 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	Benign	0.24
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Benign	0.16	T;.;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.7	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
REVEL	Benign	0.20
Sift4G	Benign	0.12	T;T;T
Polyphen		0.0030	B;.;.
Vest4		0.20
MutPred		0.44		Loss of methylation at R486 (P = 0.0111);.;Loss of methylation at R486 (P = 0.0111);
MVP		0.59
ClinPred		0.52	D
GERP RS		5.5
Varity_R		0.43
gMVP		0.52

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: chr17-62496429;