1-182858115-C-T

Variant names:

• chr1-182858115-C-T
• NM_001357.5:c.685C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001357.5(DHX9):​c.685C>T​(p.Arg229*) variant causes a stop gained change. 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). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DHX9 NM_001357.5 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.34
• 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-182858115-C-T is Pathogenic according to our data. Variant chr1-182858115-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3367220.Status of the report is no_assertion_criteria_provided, 0 stars.

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.685C>T	p.Arg229*	stop_gained	Exon 8 of 28	NP_001348.2	Q08211-1
	DHX9	NR_033302.2		n.954C>T		non_coding_transcript_exon	Exon 9 of 29

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHX9	ENST00000367549.4	TSL:1 MANE Select	c.685C>T	p.Arg229*	stop_gained	Exon 8 of 28	ENSP00000356520.3	Q08211-1
	DHX9	ENST00000926361.1		c.685C>T	p.Arg229*	stop_gained	Exon 8 of 28	ENSP00000596420.1
	DHX9	ENST00000926363.1		c.685C>T	p.Arg229*	stop_gained	Exon 9 of 29	ENSP00000596422.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual developmental disorder, autosomal dominant 75 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		4.3
Vest4		0.92
GERP RS		5.3
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Mutation Taster		=2/198	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr1-182827250; COSMIC: COSV100841370; COSMIC: COSV100841370;