rs1060499733

Positions:

• chr3-47846757-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_138615.3(DHX30):​c.1685A>G​(p.His562Arg) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DHX30 NM_138615.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 9.10

Genes affected

DHX30 (HGNC:16716): (DExH-box helicase 30) DEAD box proteins, 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. The family member encoded by this gene is a mitochondrial nucleoid protein that associates with mitochondrial DNA. It has also been identified as a component of a transcriptional repressor complex that functions in retinal development, and it is required to optimize the function of the zinc-finger antiviral protein. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2013]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a domain Helicase ATP-binding (size 168) in uniprot entity DHX30_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_138615.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DHX30. . Gene score misZ 5.2961 (greater than the threshold 3.09). Trascript score misZ 6.8999 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with severe motor impairment and absent language.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 3-47846757-A-G is Pathogenic according to our data. Variant chr3-47846757-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 402130.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-47846757-A-G is described in Lovd as [Pathogenic]. Variant chr3-47846757-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHX30	NM_138615.3	c.1685A>G	p.His562Arg	missense_variant	11/22	ENST00000445061.6	NP_619520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHX30	ENST00000445061.6	c.1685A>G	p.His562Arg	missense_variant	11/22	1	NM_138615.3	ENSP00000405620.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Sleep abnormality;C0038379:Strabismus;C0454644:Delayed speech and language development;C0557874:Global developmental delay;C1384666:Hearing impairment;C1853743:Axial hypotonia;C4551563:Microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

-

This variant was identified as de novo in an individual with developmental delay, speech delay, sleep disturbance, microcephaly, truncal and orofacial hypotonia, strabismus on the right, hyperopia, and bilateral hearing loss. -

Autism;C0948163:Abnormal cerebral white matter morphology;C3714756:Intellectual disability Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

-

- -

Neurodevelopmental disorder with severe motor impairment and absent language Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;T;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	.;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	3.8	H;.;H;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.7	D;D;.;.;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;D;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.96
MutPred		0.88		Gain of relative solvent accessibility (P = 0.1259);.;Gain of relative solvent accessibility (P = 0.1259);.;.;
MVP		0.81
MPC		2.2
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.84
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1060499733; hg19: chr3-47888247;