7-44566490-G-C

Position:

• chr7-44566490-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_019082.4(DDX56):​c.1524C>G​(p.His508Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000905 in 1,568,406 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: 𝑓 0.00012 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: DDX56 NM_019082.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0750

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011928022).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDX56	NM_019082.4	c.1524C>G	p.His508Gln	missense_variant	13/14	ENST00000258772.10	NP_061955.1
DDX56	NM_001257189.2	c.1404C>G	p.His468Gln	missense_variant	12/13		NP_001244118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX56	ENST00000258772.10	c.1524C>G	p.His508Gln	missense_variant	13/14	1	NM_019082.4	ENSP00000258772	P1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 151986 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000157 AC: 29 AN: 184934 Hom.: 0 AF XY: 0.000152 AC XY: 15 AN XY: 98486

Gnomad AFR exome AF: 0.0000971

Gnomad AMR exome AF: 0.000322

Gnomad ASJ exome AF: 0.00136

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000553

Gnomad NFE exome AF: 0.0000387

Gnomad OTH exome AF: 0.000607

GnomAD4 exome AF: 0.0000876 AC: 124 AN: 1416302 Hom.: 0 Cov.: 30 AF XY: 0.0000857 AC XY: 60 AN XY: 700298

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000361

Gnomad4 ASJ exome AF: 0.000946

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000198

Gnomad4 NFE exome AF: 0.0000708

Gnomad4 OTH exome AF: 0.000136

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152104 Hom.: 0 Cov.: 30 AF XY: 0.0000672 AC XY: 5 AN XY: 74350

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000192 Hom.: 0

Bravo AF: 0.000170

ExAC AF: 0.000119 AC: 14

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

Nov 21, 2022

The c.1524C>G (p.H508Q) alteration is located in exon 13 (coding exon 13) of the DDX56 gene. This alteration results from a C to G substitution at nucleotide position 1524, causing the histidine (H) at amino acid position 508 to be replaced by a glutamine (Q). 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	0.077
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	10
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0087	T;.;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.52	T;T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.62	N;N;N
REVEL	Benign	0.035
Sift	Benign	0.62	T;T;T
Sift4G	Benign	0.71	T;T;T
Polyphen		0.090	B;.;.
Vest4		0.33
MutPred		0.19		Gain of loop (P = 0.069);.;.;
MVP		0.067
MPC		0.15
ClinPred		0.0091	T
GERP RS		-0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs199514187; hg19: chr7-44606089;