3-47848235-GC-AT

Variant names:

• chr3-47848235-GC-AT
• NM_138615.3:c.2342_2343delGCinsAT
• DHX30 p.Gly781Asp

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS1 PM1 PP3

The NM_138615.3(DHX30):​c.2342_2343delGCinsAT​(p.Gly781Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DHX30 NM_138615.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.91
• Publications: 0 publications found

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: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

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

• PS1: Transcript NM_138615.3 (DHX30) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_138615.3
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHX30	NM_138615.3	MANE Select	c.2342_2343delGCinsAT	p.Gly781Asp	missense	N/A	NP_619520.1	Q7L2E3-1
	DHX30	NM_001330990.2		c.2258_2259delGCinsAT	p.Gly753Asp	missense	N/A	NP_001317919.1	H7BXY3
	DHX30	NM_014966.4		c.2225_2226delGCinsAT	p.Gly742Asp	missense	N/A	NP_055781.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHX30	ENST00000445061.6	TSL:1 MANE Select	c.2342_2343delGCinsAT	p.Gly781Asp	missense	N/A	ENSP00000405620.1	Q7L2E3-1
	DHX30	ENST00000395745.6	TSL:1	n.*2242_*2243delGCinsAT		non_coding_transcript_exon	Exon 16 of 23	ENSP00000379094.2	F6R0H4
	DHX30	ENST00000395745.6	TSL:1	n.*2242_*2243delGCinsAT		3_prime_UTR	Exon 16 of 23	ENSP00000379094.2	F6R0H4

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr3-47889725;