chrX-63706394-C-A

Variant names:

• chrX-63706394-C-A
• rs797045261
• NM_001353921.2:c.266G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001353921.2(ARHGEF9):​c.266G>T​(p.Gly89Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,093,630 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: ARHGEF9 NM_001353921.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.28
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF9	NM_001353921.2	MANE Select	c.266G>T	p.Gly89Val	missense	Exon 3 of 10	NP_001340850.1
	ARHGEF9	NM_001353923.1		c.284G>T	p.Gly95Val	missense	Exon 3 of 10	NP_001340852.1
	ARHGEF9	NM_001369030.1		c.245G>T	p.Gly82Val	missense	Exon 4 of 11	NP_001355959.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF9	ENST00000671741.2	MANE Select	c.266G>T	p.Gly89Val	missense	Exon 3 of 10	ENSP00000500715.1
	ARHGEF9	ENST00000253401.10	TSL:1	c.245G>T	p.Gly82Val	missense	Exon 3 of 10	ENSP00000253401.6
	ARHGEF9	ENST00000374878.5	TSL:1	c.266G>T	p.Gly89Val	missense	Exon 3 of 10	ENSP00000364012.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1093630 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 1 AN XY: 359694

African (AFR) AF: 0.00 AC: 0 AN: 26283

American (AMR) AF: 0.00 AC: 0 AN: 34985

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19293

East Asian (EAS) AF: 0.00 AC: 0 AN: 29903

South Asian (SAS) AF: 0.00 AC: 0 AN: 53067

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4096

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 840055

Other (OTH) AF: 0.00 AC: 0 AN: 45912

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Apr 23, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Apr 17, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.26
Sift	Benign	0.039	D
Sift4G	Benign	0.24	T
Polyphen		0.080	B
Vest4		0.66
MutPred		0.40		Loss of disorder (P = 0.05)
MVP		0.85
MPC		1.2
ClinPred		0.83	D
GERP RS		5.7
Varity_R		0.74
gMVP		0.94
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

dbSNP: rs797045261; hg19: chrX-62926274;