17-5450922-G-A

Variant summary

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

The NM_020162.4(DHX33):c.1409C>T(p.Ala470Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,613,860 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: DHX33 NM_020162.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.37

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=0.10926488).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHX33	NM_020162.4	c.1409C>T	p.Ala470Val	missense_variant	9/12	ENST00000225296.8
DHX33	NM_001199699.2	c.890C>T	p.Ala297Val	missense_variant	8/11
DHX33	XM_017024877.2	c.125C>T	p.Ala42Val	missense_variant	5/8
DHX33	XM_047436418.1	c.1397-516C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHX33	ENST00000225296.8	c.1409C>T	p.Ala470Val	missense_variant	9/12	1	NM_020162.4	P1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152102 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000135 AC: 34 AN: 251090 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135706

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.0000534 AC: 78 AN: 1461640 Hom.: 0 Cov.: 32 AF XY: 0.0000509 AC XY: 37 AN XY: 727126

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74434

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.000865

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

Alfa AF: 0.000248 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.0000546

EpiControl AF: 0.000178

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

Feb 16, 2023

The c.1409C>T (p.A470V) alteration is located in exon 9 (coding exon 9) of the DHX33 gene. This alteration results from a C to T substitution at nucleotide position 1409, causing the alanine (A) at amino acid position 470 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	0.18
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.029	T;T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.19
Sift	Benign	0.17	T;T
Sift4G	Benign	0.29	T;D
Polyphen		0.59	P;D
Vest4		0.41
MutPred		0.56		Loss of disorder (P = 0.0838);.;
MVP		0.60
MPC		0.24
ClinPred		0.18	T
GERP RS		5.8
Varity_R		0.23
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs575332567; hg19: chr17-5354242;