chrX-63785142-G-A

Variant names:

• chrX-63785142-G-A
• rs397514460
• NM_001353921.2:c.4C>T

Variant summary

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

The NM_001353921.2(ARHGEF9):​c.4C>T​(p.Gln2*) variant causes a stop gained change involving the alteration of a non-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: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: ARHGEF9 NM_001353921.2 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.57
• Publications: 4 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 43 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-63785142-G-A is Pathogenic according to our data. Variant chrX-63785142-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 29968.Status of the report is no_assertion_criteria_provided, 0 stars.

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.4C>T	p.Gln2*	stop_gained	Exon 1 of 10	NP_001340850.1	A0A5F9ZHY9
	ARHGEF9	NM_001353922.2		c.4C>T	p.Gln2*	stop_gained	Exon 1 of 9	NP_001340851.1
	ARHGEF9	NM_001173479.2		c.4C>T	p.Gln2*	stop_gained	Exon 1 of 9	NP_001166950.1	O43307-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF9	ENST00000671741.2	MANE Select	c.4C>T	p.Gln2*	stop_gained	Exon 1 of 10	ENSP00000500715.1	A0A5F9ZHY9
	ARHGEF9	ENST00000374878.5	TSL:1	c.4C>T	p.Gln2*	stop_gained	Exon 1 of 10	ENSP00000364012.2	B1AMR4
	ARHGEF9	ENST00000922913.1		c.4C>T	p.Gln2*	stop_gained	Exon 1 of 10	ENSP00000592972.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1051601 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 343165

African (AFR) AF: 0.00 AC: 0 AN: 24874

American (AMR) AF: 0.00 AC: 0 AN: 27835

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18587

East Asian (EAS) AF: 0.00 AC: 0 AN: 27059

South Asian (SAS) AF: 0.00 AC: 0 AN: 49660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4079

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 818452

Other (OTH) AF: 0.00 AC: 0 AN: 44283

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Developmental and epileptic encephalopathy, 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.57	D
PhyloP100		3.6
Vest4		0.61
GERP RS		4.4
PromoterAI		0.0060	Neutral
Mutation Taster		=19/181	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs397514460; hg19: chrX-63005022;