17-64500143-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_004396.5(DDX5):c.1625A>G(p.Asn542Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,614,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: DDX5 NM_004396.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94

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 Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DDX5
• BP4: Computational evidence support a benign effect (MetaRNN=0.048647583).
• BS2: High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDX5	NM_004396.5	c.1625A>G	p.Asn542Ser	missense_variant	13/13	ENST00000225792.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDX5	ENST00000225792.10	c.1625A>G	p.Asn542Ser	missense_variant	13/13	1	NM_004396.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000143 AC: 36 AN: 251444 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135902

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000132 AC: 193 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.000127 AC XY: 92 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000806

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.0000656 AC: 10 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74506

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000979 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.000123 AC: 15

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

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 06, 2021

The c.1625A>G (p.N542S) alteration is located in exon 13 (coding exon 13) of the DDX5 gene. This alteration results from a A to G substitution at nucleotide position 1625, causing the asparagine (N) at amino acid position 542 to be replaced by a serine (S). 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	0.053
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	20
Dann	Benign	0.90
DEOGEN2	Benign	0.12	T;.;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.049	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.95	L;.;.
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Uncertain	0.67	T
REVEL	Benign	0.20
Sift4G	Benign	0.47	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.26
MVP		0.43
ClinPred		0.28	T
GERP RS		6.0
Varity_R		0.085
gMVP		0.39

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

LitVar

Other links and lift over

dbSNP: rs200823006; hg19: chr17-62496261; COSMIC: COSV56751072; COSMIC: COSV56751072;