10-68901439-G-A

Position:

• chr10-68901439-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_024045.2(DDX50):​c.55G>A​(p.Glu19Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,575,810 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (8 hom.)
• Consequence: DDX50 NM_024045.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.09

Genes affected

DDX50 (HGNC:17906): (DExD-box helicase 50) 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 DEAD box protein family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box enzyme that may be involved in ribosomal RNA synthesis or processing. This gene and DDX21, also called RH-II/GuA, have similar genomic structures and are in tandem orientation on chromosome 10, suggesting that the two genes arose by gene duplication in evolution. This gene has pseudogenes on chromosomes 2, 3 and 4. Alternative splicing of this gene generates multiple transcript variants, but the full length nature of all the other variants but one has not been defined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038379729).
• BS2: High Homozygotes in GnomAdExome4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDX50	NM_024045.2	c.55G>A	p.Glu19Lys	missense_variant	1/15	ENST00000373585.8	NP_076950.1
DDX50	XM_011540144.3	c.-195G>A		5_prime_UTR_variant	1/16		XP_011538446.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX50	ENST00000373585.8	c.55G>A	p.Glu19Lys	missense_variant	1/15	1	NM_024045.2	ENSP00000362687.3
DDX50	ENST00000471475.1	n.55G>A		non_coding_transcript_exon_variant	1/6	5		ENSP00000474314.1
DDX50	ENST00000483593.5	n.55G>A		non_coding_transcript_exon_variant	1/7	3		ENSP00000474785.1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152242 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00320

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000955

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00134 AC: 252 AN: 188330 Hom.: 3 AF XY: 0.00130 AC XY: 131 AN XY: 100890

Gnomad AFR exome AF: 0.000184

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00650

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000570

Gnomad FIN exome AF: 0.00218

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.00142

GnomAD4 exome AF: 0.00124 AC: 1772 AN: 1423450 Hom.: 8 Cov.: 30 AF XY: 0.00118 AC XY: 834 AN XY: 704738

Gnomad4 AFR exome AF: 0.000124

Gnomad4 AMR exome AF: 0.00137

Gnomad4 ASJ exome AF: 0.00622

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000618

Gnomad4 FIN exome AF: 0.00151

Gnomad4 NFE exome AF: 0.00124

Gnomad4 OTH exome AF: 0.00132

GnomAD4 genome AF: 0.00108 AC: 165 AN: 152360 Hom.: 1 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74510

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.000955

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00146 Hom.: 2

Bravo AF: 0.00129

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000700 AC: 6

ExAC AF: 0.00103 AC: 124

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

Feb 10, 2023

The c.55G>A (p.E19K) alteration is located in exon 1 (coding exon 1) of the DDX50 gene. This alteration results from a G to A substitution at nucleotide position 55, causing the glutamic acid (E) at amino acid position 19 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	0.11
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.12
Sift	Benign	0.26	T
Sift4G	Benign	1.0	T
Polyphen		0.28	B
Vest4		0.30
MVP		0.36
MPC		0.56
ClinPred		0.056	T
GERP RS		4.7
Varity_R		0.28
gMVP		0.15

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: rs147182520; hg19: chr10-70661195;