17-5468825-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020162.4(DHX33):​c.35G>A​(p.Arg12Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000318 in 1,574,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DHX33
NM_020162.4 missense

Scores

1
1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.227
Variant links:
Genes affected
DHX33 (HGNC:16718): (DEAH-box helicase 33) This gene encodes a member of the DEAD box protein family. The DEAD box proteins are 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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.06272283).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DHX33NM_020162.4 linkc.35G>A p.Arg12Lys missense_variant Exon 1 of 12 ENST00000225296.8 NP_064547.2 Q9H6R0-1B4DIS6
DHX33XM_047436418.1 linkc.35G>A p.Arg12Lys missense_variant Exon 1 of 9 XP_047292374.1
DHX33NM_001199699.2 linkc.-324G>A 5_prime_UTR_variant Exon 1 of 11 NP_001186628.1 Q9H6R0-2B4DIS6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DHX33ENST00000225296.8 linkc.35G>A p.Arg12Lys missense_variant Exon 1 of 12 1 NM_020162.4 ENSP00000225296.3 Q9H6R0-1
DHX33ENST00000433302.7 linkc.35G>A p.Arg12Lys missense_variant Exon 1 of 8 1 ENSP00000413779.3 Q05BE5
DHX33ENST00000574023.1 linkn.5G>A non_coding_transcript_exon_variant Exon 1 of 11 1 ENSP00000458203.1 I3L0M5
DHX33ENST00000572490.1 linkc.-78G>A upstream_gene_variant 1 ENSP00000458925.1 I3L1L6

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152226
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000115
AC:
2
AN:
173842
Hom.:
0
AF XY:
0.0000208
AC XY:
2
AN XY:
96002
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000749
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000211
AC:
3
AN:
1422568
Hom.:
0
Cov.:
32
AF XY:
0.00000284
AC XY:
2
AN XY:
704412
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000783
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152226
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74376
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 26, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.35G>A (p.R12K) alteration is located in exon 1 (coding exon 1) of the DHX33 gene. This alteration results from a G to A substitution at nucleotide position 35, causing the arginine (R) at amino acid position 12 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
0.19
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.0039
T;T
Eigen
Benign
-0.55
Eigen_PC
Benign
-0.38
FATHMM_MKL
Benign
0.17
N
LIST_S2
Benign
0.57
T;T
M_CAP
Benign
0.043
D
MetaRNN
Benign
0.063
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N;.
PrimateAI
Pathogenic
0.90
D
PROVEAN
Benign
-0.040
N;N
REVEL
Benign
0.10
Sift
Benign
0.30
T;D
Sift4G
Benign
0.64
T;T
Polyphen
0.0
B;B
Vest4
0.20
MutPred
0.24
Gain of ubiquitination at R12 (P = 0.0104);Gain of ubiquitination at R12 (P = 0.0104);
MVP
0.38
MPC
0.24
ClinPred
0.12
T
GERP RS
4.0
Varity_R
0.27
gMVP
0.43

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: rs779864363; hg19: chr17-5372145; API