rs1556301016

Variant names:

• chrX-63638120-C-T
• rs1556301016
• NM_001353921.2:c.1480G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001353921.2(ARHGEF9):​c.1480G>A​(p.Ala494Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,094,222 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A494A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000010 (0 hom. 5 hem.)
• Consequence: ARHGEF9 NM_001353921.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.11
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12630245).
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL gene

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.1480G>A	p.Ala494Thr	missense	Exon 10 of 10	NP_001340850.1	A0A5F9ZHY9
	ARHGEF9	NM_001353923.1		c.1498G>A	p.Ala500Thr	missense	Exon 10 of 10	NP_001340852.1	A0A1B0GWI5
	ARHGEF9	NM_001369030.1		c.1459G>A	p.Ala487Thr	missense	Exon 11 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.1480G>A	p.Ala494Thr	missense	Exon 10 of 10	ENSP00000500715.1	A0A5F9ZHY9
	ARHGEF9	ENST00000253401.10	TSL:1	c.1459G>A	p.Ala487Thr	missense	Exon 10 of 10	ENSP00000253401.6	O43307-1
	ARHGEF9	ENST00000624843.3	TSL:1	c.1153G>A	p.Ala385Thr	missense	Exon 9 of 9	ENSP00000485626.1	O43307-3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000574 AC: 1 AN: 174340 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000374

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000101 AC: 11 AN: 1094222 Hom.: 0 Cov.: 31 AF XY: 0.0000139 AC XY: 5 AN XY: 359856

African (AFR) AF: 0.00 AC: 0 AN: 26360

American (AMR) AF: 0.0000574 AC: 2 AN: 34860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19333

East Asian (EAS) AF: 0.00 AC: 0 AN: 30085

South Asian (SAS) AF: 0.00 AC: 0 AN: 53152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.0000107 AC: 9 AN: 840076

Other (OTH) AF: 0.00 AC: 0 AN: 45966

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.084	T
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.096
Sift	Uncertain	0.023	D
Sift4G	Benign	0.098	T
Polyphen		0.048	B
Vest4		0.039
MutPred		0.22		Gain of glycosylation at A487 (P = 0.0273)
MVP		0.77
MPC		0.99
ClinPred		0.21	T
GERP RS		4.3
Varity_R		0.14
gMVP		0.70
Mutation Taster		=83/17	polymorphism

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: rs1556301016; hg19: chrX-62858000;