17-5468735-C-A

Variant names:

• chr17-5468735-C-A
• rs992788931
• NM_020162.4:c.125G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020162.4(DHX33):​c.125G>T​(p.Gly42Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000891 in 1,458,772 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G42S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: DHX33 NM_020162.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.71

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14396077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHX33	NM_020162.4	c.125G>T	p.Gly42Val	missense_variant	Exon 1 of 12	ENST00000225296.8	NP_064547.2
DHX33	XM_047436418.1	c.125G>T	p.Gly42Val	missense_variant	Exon 1 of 9		XP_047292374.1
DHX33	NM_001199699.2	c.-234G>T		5_prime_UTR_variant	Exon 1 of 11		NP_001186628.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHX33	ENST00000225296.8	c.125G>T	p.Gly42Val	missense_variant	Exon 1 of 12	1	NM_020162.4	ENSP00000225296.3
DHX33	ENST00000572490.1	c.13G>T	p.Ala5Ser	missense_variant	Exon 1 of 11	1		ENSP00000458925.1
DHX33	ENST00000433302.7	c.125G>T	p.Gly42Val	missense_variant	Exon 1 of 8	1		ENSP00000413779.3
DHX33	ENST00000574023.1	n.95G>T		non_coding_transcript_exon_variant	Exon 1 of 11	1		ENSP00000458203.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000891 AC: 13 AN: 1458772 Hom.: 0 Cov.: 32 AF XY: 0.00000965 AC XY: 7 AN XY: 725504

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000990

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000469 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.125G>T (p.G42V) alteration is located in exon 1 (coding exon 1) of the DHX33 gene. This alteration results from a G to T substitution at nucleotide position 125, causing the glycine (G) at amino acid position 42 to be replaced by a valine (V). 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	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Benign	0.012	T;T
Eigen	Benign	-0.076
Eigen_PC	Benign	0.060
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.94	N;N
REVEL	Benign	0.075
Sift	Benign	0.031	D;D
Sift4G	Uncertain	0.030	D;D
Polyphen		0.27	B;P
Vest4		0.26
MutPred		0.34		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);
MVP		0.64
MPC		0.32
ClinPred		0.36	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.22
gMVP		0.49

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: rs992788931; hg19: chr17-5372055;