7-44566464-G-A

Position:

• chr7-44566464-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019082.4(DDX56):​c.1550C>T​(p.Ser517Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,407,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: DDX56 NM_019082.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.78

Genes affected

DDX56 (HGNC:18193): (DEAD-box helicase 56) This gene encodes a member of the DEAD box protein family. 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 this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. The protein encoded by this gene shows ATPase activity in the presence of polynucleotides and associates with nucleoplasmic 65S preribosomal particles. This gene may be involved in ribosome synthesis, most likely during assembly of the large 60S ribosomal subunit. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07097426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDX56	NM_019082.4	c.1550C>T	p.Ser517Phe	missense_variant	13/14	ENST00000258772.10	NP_061955.1
DDX56	NM_001257189.2	c.1430C>T	p.Ser477Phe	missense_variant	12/13		NP_001244118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX56	ENST00000258772.10	c.1550C>T	p.Ser517Phe	missense_variant	13/14	1	NM_019082.4	ENSP00000258772.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1407008 Hom.: 0 Cov.: 30 AF XY: 0.00000144 AC XY: 1 AN XY: 694878

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.23e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

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

Jan 31, 2024

The c.1550C>T (p.S517F) alteration is located in exon 13 (coding exon 13) of the DDX56 gene. This alteration results from a C to T substitution at nucleotide position 1550, causing the serine (S) at amino acid position 517 to be replaced by a phenylalanine (F). 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	0.097
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T;.;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.54	T;T;T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.071	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	2.0	M;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.045
Sift	Benign	0.048	D;D;T
Sift4G	Uncertain	0.042	D;D;D
Polyphen		0.14	B;.;.
Vest4		0.33
MutPred		0.29		Loss of phosphorylation at S517 (P = 0.0036);.;.;
MVP		0.17
MPC		0.18
ClinPred		0.26	T
GERP RS		2.4
Varity_R		0.033
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs769140577; hg19: chr7-44606063; COSMIC: COSV51838145; COSMIC: COSV51838145;