rs1057519436

Positions:

• chr3-47846550-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_138615.3(DHX30):​c.1478G>A​(p.Arg493His) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DHX30 NM_138615.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:3
• Conservation: PhyloP100: 9.91

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 10 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, 0.975
• PP5: Variant 3-47846550-G-A is Pathogenic according to our data. Variant chr3-47846550-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 375374.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-47846550-G-A is described in Lovd as [Pathogenic]. Variant chr3-47846550-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHX30	NM_138615.3	c.1478G>A	p.Arg493His	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.1478G>A	p.Arg493His	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: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 27, 2023

- -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

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- -

Seizure;C0038379:Strabismus;C0231686:Unsteady gait;C0349588:Short stature;C3489733:Oculomotor apraxia;C4551563:Microcephaly Pathogenic:1

Pathogenic, no assertion criteria provided

research

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

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This variant was identified as de novo in an individual with seizures, microcephaly, short stature, strabismus, oculomotor apraxia, unsteady gait. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T;T;T;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	3.8	H;.;H;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.8	D;D;.;.;D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;D;.;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.90
MutPred		0.92		Loss of MoRF binding (P = 0.0205);.;Loss of MoRF binding (P = 0.0205);.;.;
MVP		0.57
MPC		2.3
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.84
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519436; hg19: chr3-47888040; COSMIC: COSV53140099; COSMIC: COSV53140099;