4-24542948-T-C

Variant names:

• chr4-24542948-T-C
• NM_001358.3:c.1327A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001358.3(DHX15):​c.1327A>G​(p.Lys443Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DHX15 NM_001358.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.64
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001358.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHX15	NM_001358.3	MANE Select	c.1327A>G	p.Lys443Glu	missense	Exon 7 of 14	NP_001349.2	O43143

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHX15	ENST00000336812.5	TSL:1 MANE Select	c.1327A>G	p.Lys443Glu	missense	Exon 7 of 14	ENSP00000336741.4	O43143
	DHX15	ENST00000853185.1		c.1318A>G	p.Lys440Glu	missense	Exon 7 of 14	ENSP00000523244.1
	DHX15	ENST00000853187.1		c.1327A>G	p.Lys443Glu	missense	Exon 7 of 14	ENSP00000523246.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Patent ductus arteriosus;C0026351:Moderate intellectual disability;C0036572:Seizure;C0266491:Gray matter heterotopia;C0424503:Abnormal facial shape;C0454644:Delayed speech and language development;C4022908:Cerebral white matter hypoplasia;C5399973:Periventricular heterotopia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	4.4	H
PhyloP100		7.6
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.78		Loss of methylation at K443 (P = 0.0071)
MVP		0.90
MPC		3.5
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.87
gMVP		0.99
Mutation Taster		=44/56	disease causing

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

hg19: chr4-24544571; COSMIC: COSV61028989; COSMIC: COSV61028989;