17-5450869-G-C

Variant summary

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

The NM_020162.4(DHX33):c.1462C>G(p.Leu488Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DHX33 NM_020162.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.69

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=0.08480862).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHX33	NM_020162.4	c.1462C>G	p.Leu488Val	missense_variant	9/12	ENST00000225296.8
DHX33	NM_001199699.2	c.943C>G	p.Leu315Val	missense_variant	8/11
DHX33	XM_017024877.2	c.178C>G	p.Leu60Val	missense_variant	5/8
DHX33	XM_047436418.1	c.1397-463C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHX33	ENST00000225296.8	c.1462C>G	p.Leu488Val	missense_variant	9/12	1	NM_020162.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

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

Apr 07, 2022

The c.1462C>G (p.L488V) alteration is located in exon 9 (coding exon 9) of the DHX33 gene. This alteration results from a C to G substitution at nucleotide position 1462, causing the leucine (L) at amino acid position 488 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	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0076	T;T
Eigen	Benign	0.061
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.085	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.14	N;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.34	N;N
REVEL	Benign	0.067
Sift	Benign	0.55	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.0090	B;B
Vest4		0.047
MutPred		0.61		Gain of helix (P = 0.0425);.;
MVP		0.65
MPC		0.25
ClinPred		0.43	T
GERP RS		5.8
Varity_R		0.053
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1366329523; hg19: chr17-5354189;