rs1057519436

Variant names:

• chr3-47846550-G-A
• rs1057519436
• NM_138615.3:c.1478G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 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 Likely_pathogenic. Variant got 9 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
• 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 rank	MANE	Protein	UniProt
DHX30	NM_138615.3	c.1478G>A	p.Arg493His	missense_variant	Exon 11 of 22	ENST00000445061.6	NP_619520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHX30	ENST00000445061.6	c.1478G>A	p.Arg493His	missense_variant	Exon 11 of 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

Feb 27, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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;