12-48830668-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_004818.3(DDX23):​c.2264C>T​(p.Thr755Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

DDX23
NM_004818.3 missense

Scores

16
2
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 9.85
Variant links:
Genes affected
DDX23 (HGNC:17347): (DEAD-box helicase 23) 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 is a component of the U5 snRNP complex; it may facilitate conformational changes in the spliceosome during nuclear pre-mRNA splicing. An alternatively spliced transcript variant has been found for this gene, but its biological validity has not been determined. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.976
PP5
Variant 12-48830668-G-A is Pathogenic according to our data. Variant chr12-48830668-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 862674.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DDX23NM_004818.3 linkc.2264C>T p.Thr755Met missense_variant Exon 17 of 17 ENST00000308025.8 NP_004809.2 Q9BUQ8-1A0A024R0Z3B3KY11

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DDX23ENST00000308025.8 linkc.2264C>T p.Thr755Met missense_variant Exon 17 of 17 1 NM_004818.3 ENSP00000310723.2 Q9BUQ8-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:1
Nov 10, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces threonine with methionine at codon 755 of the DDX23 protein (p.Thr755Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of DDX23-related neurodevelopmental disorder (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 862674). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Aug 10, 2020
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.85
D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.87
D
M_CAP
Pathogenic
0.63
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Uncertain
0.65
D
MutationAssessor
Pathogenic
4.5
H
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-5.0
D
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.99
D
Vest4
0.86
MutPred
0.88
Gain of MoRF binding (P = 0.0744);
MVP
0.94
MPC
2.6
ClinPred
1.0
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.77
gMVP
0.95

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1938372282; hg19: chr12-49224451; API