chrX-63638126-C-T

Variant names:

• chrX-63638126-C-T
• rs1365914320
• NM_001353921.2:c.1474G>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.1474G>A​(p.Gly492Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000581 in 1,204,553 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
• Consequence: ARHGEF9 NM_001353921.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.51

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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09782162).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF9	NM_001353921.2	c.1474G>A	p.Gly492Ser	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.1474G>A	p.Gly492Ser	missense_variant	Exon 10 of 10		NM_001353921.2	ENSP00000500715.1

Frequencies

GnomAD3 genomes AF: 0.00000903 AC: 1 AN: 110765 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000580 AC: 1 AN: 172493 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000755

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000549 AC: 6 AN: 1093788 Hom.: 0 Cov.: 31 AF XY: 0.00000556 AC XY: 2 AN XY: 359482

African (AFR) AF: 0.00 AC: 0 AN: 26343

American (AMR) AF: 0.00 AC: 0 AN: 34802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19330

East Asian (EAS) AF: 0.0000665 AC: 2 AN: 30062

South Asian (SAS) AF: 0.0000565 AC: 3 AN: 53078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40233

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

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 839858

Other (OTH) AF: 0.00 AC: 0 AN: 45953

GnomAD4 genome AF: 0.00000903 AC: 1 AN: 110765 Hom.: 0 Cov.: 22 AF XY: 0.0000303 AC XY: 1 AN XY: 33015

African (AFR) AF: 0.00 AC: 0 AN: 30388

American (AMR) AF: 0.00 AC: 0 AN: 10325

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2628

East Asian (EAS) AF: 0.00 AC: 0 AN: 3535

South Asian (SAS) AF: 0.00 AC: 0 AN: 2577

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5892

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 53003

Other (OTH) AF: 0.00 AC: 0 AN: 1499

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 18, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autism spectrum disorder Uncertain:1

Dec 01, 2019

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 8 Uncertain:1

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 485 of the ARHGEF9 protein (p.Gly485Ser). 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 missense change has been observed in individuals with ARHGEF9-related conditions (PMID: 35217970; internal data). ClinVar contains an entry for this variant (Variation ID: 579449). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ARHGEF9 protein function with a negative predictive value of 95%. This variant disrupts the p.Gly485 amino acid residue in ARHGEF9. Other variant(s) that disrupt this residue have been observed in individuals with ARHGEF9-related conditions (PMID: 31780880, 35217970), which suggests that this may be a clinically significant amino acid residue. 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	0.072
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Benign	0.43
DEOGEN2	Benign	0.066	T;.;T;T;T;T;T;T;.;T;.;T;T;.;T;.;T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;.;D;.;.;.;D;.;D;.;.;D;.;D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.098	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.33	N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	1.4	N;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.
REVEL	Benign	0.18
Sift	Benign	1.0	T;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.
Sift4G	Benign	1.0	T;T;.;.;.;.;.;.;T;T;.;.;.;.;T;T;.
Polyphen		0.0040	B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.11
MutPred		0.25		Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.70
MPC		1.0
ClinPred		0.22	T
GERP RS		5.5
Varity_R		0.32
gMVP		0.76
Mutation Taster		=74/26	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

Publications

LitVar

Other links and lift over

dbSNP: rs1365914320; hg19: chrX-62858006; COSMIC: COSV53639831; COSMIC: COSV53639831;