chrX-63697256-G-C

Variant names:

• chrX-63697256-G-C
• rs781955551
• NM_001353921.2:c.451C>G

Variant summary

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

The NM_001353921.2(ARHGEF9):​c.451C>G​(p.Gln151Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,168 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. Q151K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: ARHGEF9 NM_001353921.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.35
• 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 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF9	NM_001353921.2	MANE Select	c.451C>G	p.Gln151Glu	missense	Exon 4 of 10	NP_001340850.1	A0A5F9ZHY9
	ARHGEF9	NM_001353923.1		c.469C>G	p.Gln157Glu	missense	Exon 4 of 10	NP_001340852.1	A0A1B0GWI5
	ARHGEF9	NM_001369030.1		c.430C>G	p.Gln144Glu	missense	Exon 5 of 11	NP_001355959.1	O43307-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF9	ENST00000671741.2	MANE Select	c.451C>G	p.Gln151Glu	missense	Exon 4 of 10	ENSP00000500715.1	A0A5F9ZHY9
	ARHGEF9	ENST00000253401.10	TSL:1	c.430C>G	p.Gln144Glu	missense	Exon 4 of 10	ENSP00000253401.6	O43307-1
	ARHGEF9	ENST00000374878.5	TSL:1	c.451C>G	p.Gln151Glu	missense	Exon 4 of 10	ENSP00000364012.2	B1AMR4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097168 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 362720

African (AFR) AF: 0.00 AC: 0 AN: 26367

American (AMR) AF: 0.00 AC: 0 AN: 35159

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19365

East Asian (EAS) AF: 0.00 AC: 0 AN: 30198

South Asian (SAS) AF: 0.00 AC: 0 AN: 54113

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841288

Other (OTH) AF: 0.00 AC: 0 AN: 46049

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.88	L
PhyloP100		9.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.24
Sift	Benign	0.050	D
Sift4G	Benign	0.25	T
Polyphen		0.92	P
Vest4		0.59
MutPred		0.54		Gain of phosphorylation at S141 (P = 0.0979)
MVP		0.86
MPC		1.4
ClinPred		0.93	D
GERP RS		5.6
Varity_R		0.59
gMVP		0.82
Mutation Taster		=11/89	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: rs781955551; hg19: chrX-62917136;