chrX-63697117-ATACT-A

Variant names:

• chrX-63697117-ATACT-A
• NM_001353921.2:c.582+4_582+7delAGTA

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001353921.2(ARHGEF9):​c.582+4_582+7delAGTA variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ARHGEF9 NM_001353921.2 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.36
• Publications: 0 publications found

Genes affected

ARHGEF9 (HGNC:14561): (Cdc42 guanine nucleotide exchange factor 9) The protein encoded by this gene is a Rho-like GTPase that switches between the active (GTP-bound) state and inactive (GDP-bound) state to regulate CDC42 and other genes. This brain-specific protein also acts as an adaptor protein for the recruitment of gephyrin and together these proteins facilitate receceptor recruitement in GABAnergic and glycinergic synapses. Defects in this gene are the cause of startle disease with epilepsy (STHEE), also known as hyperekplexia with epilepsy, as well as several other types of cognitive disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

ARHGEF9 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 8

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353921.2. 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
	ARHGEF9	NM_001353921.2	MANE Select	c.582+4_582+7delAGTA		splice_region intron	N/A	NP_001340850.1	A0A5F9ZHY9
	ARHGEF9	NM_001353923.1		c.600+4_600+7delAGTA		splice_region intron	N/A	NP_001340852.1	A0A1B0GWI5
	ARHGEF9	NM_001369030.1		c.561+4_561+7delAGTA		splice_region intron	N/A	NP_001355959.1	O43307-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF9	ENST00000671741.2	MANE Select	c.582+4_582+7delAGTA		splice_region intron	N/A	ENSP00000500715.1	A0A5F9ZHY9
	ARHGEF9	ENST00000253401.10	TSL:1	c.561+4_561+7delAGTA		splice_region intron	N/A	ENSP00000253401.6	O43307-1
	ARHGEF9	ENST00000374878.5	TSL:1	c.582+4_582+7delAGTA		splice_region intron	N/A	ENSP00000364012.2	B1AMR4

Frequencies

GnomAD3 genomes Cov.: 22

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

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.77		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.27		Position offset: 12
DS_DL_spliceai		0.77		Position offset: 8

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

Other links and lift over

hg19: chrX-62916997;