4-24576502-G-C

Variant names:

• chr4-24576502-G-C
• rs1341748575
• NM_001358.3:c.248C>G

Variant summary

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

The NM_001358.3(DHX15):​c.248C>G​(p.Ala83Gly) 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. 12/21 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)
• Consequence: DHX15 NM_001358.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.22

Genes affected

DHX15 (HGNC:2738): (DEAH-box helicase 15) The protein encoded by this gene is a putative ATP-dependent RNA helicase implicated in pre-mRNA splicing. [provided by RefSeq, Jul 2008]

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=0.13502258).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHX15	NM_001358.3	c.248C>G	p.Ala83Gly	missense_variant	Exon 2 of 14	ENST00000336812.5	NP_001349.2
DHX15	XM_047449698.1	c.248C>G	p.Ala83Gly	missense_variant	Exon 2 of 11		XP_047305654.1
DHX15	XM_047449699.1	c.248C>G	p.Ala83Gly	missense_variant	Exon 2 of 11		XP_047305655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHX15	ENST00000336812.5	c.248C>G	p.Ala83Gly	missense_variant	Exon 2 of 14	1	NM_001358.3	ENSP00000336741.4
DHX15	ENST00000511553.5	n.499C>G		non_coding_transcript_exon_variant	Exon 3 of 3	4
DHX15	ENST00000513092.1	n.*48C>G		downstream_gene_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.248C>G (p.A83G) alteration is located in exon 2 (coding exon 2) of the DHX15 gene. This alteration results from a C to G substitution at nucleotide position 248, causing the alanine (A) at amino acid position 83 to be replaced by a glycine (G). 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	0.080
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.012
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.34	N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.080
Sift	Benign	0.24	T
Sift4G	Benign	0.42	T
Polyphen		0.15	B
Vest4		0.28
MutPred		0.19		Gain of relative solvent accessibility (P = 0.0082);
MVP		0.35
MPC		0.95
ClinPred		0.59	D
GERP RS		5.1
Varity_R		0.091
gMVP		0.17

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: rs1341748575; hg19: chr4-24578125;