17-42103720-G-T

Variant names:

• chr17-42103720-G-T
• rs1439684490
• NM_024119.3:c.1642C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024119.3(DHX58):​c.1642C>A​(p.Pro548Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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)
• Consequence: DHX58 NM_024119.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.669
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054332107).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHX58	NM_024119.3	c.1642C>A	p.Pro548Thr	missense_variant	Exon 12 of 14	ENST00000251642.8	NP_077024.2
DHX58	XM_047436724.1	c.1642C>A	p.Pro548Thr	missense_variant	Exon 12 of 14		XP_047292680.1
DHX58	XM_047436725.1	c.1642C>A	p.Pro548Thr	missense_variant	Exon 12 of 14		XP_047292681.1
DHX58	XM_047436726.1	c.1563+1046C>A		intron_variant	Intron 11 of 11		XP_047292682.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHX58	ENST00000251642.8	c.1642C>A	p.Pro548Thr	missense_variant	Exon 12 of 14	1	NM_024119.3	ENSP00000251642.3
DHX58	ENST00000586522.5	n.1824C>A		non_coding_transcript_exon_variant	Exon 12 of 12	2
DHX58	ENST00000590637.1	n.636C>A		non_coding_transcript_exon_variant	Exon 4 of 4	5
DHX58	ENST00000589979.1	n.141+1046C>A		intron_variant	Intron 1 of 2	3		ENSP00000467470.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1642C>A (p.P548T) alteration is located in exon 12 (coding exon 10) of the DHX58 gene. This alteration results from a C to A substitution at nucleotide position 1642, causing the proline (P) at amino acid position 548 to be replaced by a threonine (T). 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	0.074
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.5
DANN	Benign	0.18
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.67
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.047
Sift	Benign	0.65	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.088
MutPred		0.40		Loss of loop (P = 0.0073);
MVP		0.33
MPC		0.27
ClinPred		0.028	T
GERP RS		3.9
Varity_R		0.17
gMVP		0.32

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

Other links and lift over

dbSNP: rs1439684490; hg19: chr17-40255738;