Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

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

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:3

Conservation

PhyloP100: 9.91

Publications

13 publications found

Variant links:

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]

DHX30 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with severe motor impairment and absent language
Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

DHX30 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

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 VariationId is 375374.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138615.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DHX30	NM_138615.3	MANE Select	c.1478G>A	p.Arg493His	missense	Exon 11 of 22	NP_619520.1
DHX30	NM_001330990.2		c.1394G>A	p.Arg465His	missense	Exon 12 of 23	NP_001317919.1
DHX30	NM_014966.4		c.1361G>A	p.Arg454His	missense	Exon 12 of 23	NP_055781.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DHX30	ENST00000445061.6	TSL:1 MANE Select	c.1478G>A	p.Arg493His	missense	Exon 11 of 22	ENSP00000405620.1
DHX30	ENST00000395745.6	TSL:1	n.*1378G>A		non_coding_transcript_exon	Exon 12 of 23	ENSP00000379094.2
DHX30	ENST00000395745.6	TSL:1	n.*1378G>A		3_prime_UTR	Exon 12 of 23	ENSP00000379094.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurodevelopmental disorder with severe motor impairment and absent language (1)

not provided (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.44

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

-0.26

MutationAssessor

Pathogenic

3.8

PhyloP100

9.9

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.90

MutPred

0.92

Loss of MoRF binding (P = 0.0205)

MVP

0.57

MPC

2.3

ClinPred

1.0

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.84

gMVP

0.98

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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rs1057519436

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over