17-42102272-T-C

Position:

• chr17-42102272-T-C

Variant summary

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

The NM_024119.3(DHX58):​c.1795A>G​(p.Lys599Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: DHX58 NM_024119.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31

Genes affected

DHX58 (HGNC:29517): (DExH-box helicase 58) Enables double-stranded RNA binding activity; single-stranded RNA binding activity; and zinc ion binding activity. Involved in negative regulation of defense response and negative regulation of type I interferon production. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DHX58 (HGNC:):

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=0.111561984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHX58	NM_024119.3	c.1795A>G	p.Lys599Glu	missense_variant	13/14	ENST00000251642.8	NP_077024.2
DHX58	XM_047436724.1	c.1795A>G	p.Lys599Glu	missense_variant	13/14		XP_047292680.1
DHX58	XM_047436725.1	c.1795A>G	p.Lys599Glu	missense_variant	13/14		XP_047292681.1
DHX58	XM_047436726.1	c.*29A>G		3_prime_UTR_variant	12/12		XP_047292682.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHX58	ENST00000251642.8	c.1795A>G	p.Lys599Glu	missense_variant	13/14	1	NM_024119.3	ENSP00000251642.3
DHX58	ENST00000589979.1	n.*29A>G		non_coding_transcript_exon_variant	2/3	3		ENSP00000467470.1
DHX58	ENST00000592024.1	n.538A>G		non_coding_transcript_exon_variant	1/2	2
DHX58	ENST00000589979.1	n.*29A>G		3_prime_UTR_variant	2/3	3		ENSP00000467470.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727248

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

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

Aug 04, 2023

The c.1795A>G (p.K599E) alteration is located in exon 13 (coding exon 11) of the DHX58 gene. This alteration results from a A to G substitution at nucleotide position 1795, causing the lysine (K) at amino acid position 599 to be replaced by a glutamic acid (E). 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	0.15
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.093
Sift	Benign	0.18	T
Sift4G	Benign	0.32	T
Polyphen		0.075	B
Vest4		0.18
MutPred		0.52		Loss of methylation at K599 (P = 0.0075);
MVP		0.59
MPC		0.41
ClinPred		0.23	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1272450118; hg19: chr17-40254290;