1-182853363-GA-TT

Variant names:

• chr1-182853363-GA-TT
• NM_001357.5:c.422_423delGAinsTT
• DHX9 p.Arg141Leu

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM5 PP2

The NM_001357.5(DHX9):​c.422_423delGAinsTT​(p.Arg141Leu) variant causes a missense change. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R141G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DHX9 NM_001357.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.67
• Publications: 0 publications found

Genes affected

DHX9 (HGNC:2750): (DExH-box helicase 9) This gene encodes a member of the DEAH-containing family of RNA helicases. The encoded protein is an enzyme that catalyzes the ATP-dependent unwinding of double-stranded RNA and DNA-RNA complexes. This protein localizes to both the nucleus and the cytoplasm and functions as a transcriptional regulator. This protein may also be involved in the expression and nuclear export of retroviral RNAs. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 11 and 13.[provided by RefSeq, Feb 2010]

DHX9 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, autosomal dominant 75

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-182853363-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3367217.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 5.8433 (above the threshold of 3.09). Trascript score misZ: 7.2163 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual developmental disorder, autosomal dominant 75.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001357.5. 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
	DHX9	NM_001357.5	MANE Select	c.422_423delGAinsTT	p.Arg141Leu	missense	N/A	NP_001348.2	Q08211-1
	DHX9	NR_033302.2		n.554_555delGAinsTT		non_coding_transcript_exon	Exon 5 of 29

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHX9	ENST00000367549.4	TSL:1 MANE Select	c.422_423delGAinsTT	p.Arg141Leu	missense	N/A	ENSP00000356520.3	Q08211-1
	DHX9	ENST00000926361.1		c.422_423delGAinsTT	p.Arg141Leu	missense	N/A	ENSP00000596420.1
	DHX9	ENST00000926363.1		c.422_423delGAinsTT	p.Arg141Leu	missense	N/A	ENSP00000596422.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7

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: chr1-182822498;