dbSNP rs1052637: DDX18:p.Thr94Asn (chr2-117817639-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006773.4(DDX18):c.281C>A(p.Thr94Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DDX18
NM_006773.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.463

Publications

39 publications found

Variant links:

Genes affected

DDX18 (HGNC:2741): (DEAD-box helicase 18) 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. This gene encodes a DEAD box protein, and it is activated by Myc protein. [provided by RefSeq, Jul 2008]

DDX18 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.064835995).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDX18	NM_006773.4 link	c.281C>A	p.Thr94Asn	missense_variant	Exon 2 of 14	ENST00000263239.7	NP_006764.3	Q9NVP1Q8N254

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX18	ENST00000263239.7 link	c.281C>A	p.Thr94Asn	missense_variant	Exon 2 of 14	1	NM_006773.4	ENSP00000263239.2		Q9NVP1
DDX18	ENST00000474694.1 link	n.267C>A		non_coding_transcript_exon_variant	Exon 3 of 9	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461528

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727074

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111796

Other (OTH)

AF:

0.0000166

AC:

AN:

60372

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

5.1

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0092

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.78

M_CAP

Benign

0.0022

MetaRNN

Benign

0.065

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

PhyloP100

0.46

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.070

REVEL

Benign

0.070

Sift

Benign

0.060

Sift4G

Benign

0.49

Polyphen

0.047

Vest4

0.13

MutPred

0.095

Loss of phosphorylation at T94 (P = 0.0522);

MVP

0.32

MPC

0.17

ClinPred

0.18

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.030

gMVP

0.11

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over