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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: MODERATE 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF9	NM_001353921.2	c.1480G>A	p.Ala494Thr	missense_variant	Exon 10 of 10	ENST00000671741.2	NP_001340850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF9	ENST00000671741.2	c.1480G>A	p.Ala494Thr	missense_variant	Exon 10 of 10		NM_001353921.2	ENSP00000500715.1

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

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 19, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1459G>A (p.A487T) alteration is located in coding exon 10 of the ARHGEF9 gene. This alteration results from a G to A substitution at nucleotide position 1459, causing the alanine (A) at amino acid position 487 to be replaced by a threonine (T). Based on data from the Genome Aggregation Database (gnomAD) database, the ARHGEF9 c.1459G>A alteration was observed in <0.01% (1/174340) of total alleles studied. This amino acid position is not well conserved in available vertebrate species. The p.A487T alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Developmental and epileptic encephalopathy, 8 Uncertain:1

Jun 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 487 of the ARHGEF9 protein (p.Ala487Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ARHGEF9-related conditions. ClinVar contains an entry for this variant (Variation ID: 533663). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ARHGEF9 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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;.;T;T;T;T;T;T;.;T;.;T;T;.;T;.;T
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.84	T;T;T;.;T;.;.;.;T;.;T;.;.;T;.;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.90	L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		2.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.16	N;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.
REVEL	Benign	0.096
Sift	Uncertain	0.023	D;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Sift4G	Benign	0.098	T;T;.;.;.;.;.;.;T;T;.;.;.;.;T;T;.
Polyphen		0.048	B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.039
MutPred		0.22		Gain of glycosylation at A487 (P = 0.0273);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;