Genetic Variant ARHGEF9:p.Glu193Glu (chrX-63697128-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_001353921.2(ARHGEF9):c.579G>A(p.Glu193Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000406 in 1,207,168 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000029 ( 0 hom. 11 hem. )

Consequence

ARHGEF9
NM_001353921.2 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.99

Publications

0 publications found

Variant links:

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

ARHGEF9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant X-63697128-C-T is Benign according to our data. Variant chrX-63697128-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 389108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.99 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 2 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARHGEF9	NM_001353921.2	MANE Select	c.579G>A	p.Glu193Glu	synonymous	Exon 4 of 10	NP_001340850.1
ARHGEF9	NM_001353923.1		c.597G>A	p.Glu199Glu	synonymous	Exon 4 of 10	NP_001340852.1
ARHGEF9	NM_001369030.1		c.558G>A	p.Glu186Glu	synonymous	Exon 5 of 11	NP_001355959.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARHGEF9	ENST00000671741.2	MANE Select	c.579G>A	p.Glu193Glu	synonymous	Exon 4 of 10	ENSP00000500715.1
ARHGEF9	ENST00000253401.10	TSL:1	c.558G>A	p.Glu186Glu	synonymous	Exon 4 of 10	ENSP00000253401.6
ARHGEF9	ENST00000374878.5	TSL:1	c.579G>A	p.Glu193Glu	synonymous	Exon 4 of 10	ENSP00000364012.2

Frequencies

GnomAD3 genomes

AF:

0.000153

AC:

AN:

111389

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000283

AC:

AN:

176647

AF XY:

0.0000161

show subpopulations

Gnomad AFR exome

AF:

0.000312

Gnomad AMR exome

AF:

0.00

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:

0.000229

GnomAD4 exome

AF:

0.0000292

AC:

AN:

1095779

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

361683

show subpopulations

African (AFR)

AF:

0.000759

AC:

AN:

26334

American (AMR)

AF:

0.00

AC:

AN:

34948

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19297

East Asian (EAS)

AF:

0.00

AC:

AN:

30141

South Asian (SAS)

AF:

0.0000558

AC:

AN:

53724

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40397

Middle Eastern (MID)

AF:

0.000244

AC:

AN:

4105

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840884

Other (OTH)

AF:

0.000174

AC:

AN:

45949

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000153

AC:

AN:

111389

Hom.:

Cov.:

AF XY:

0.0000595

AC XY:

AN XY:

33597

show subpopulations

African (AFR)

AF:

0.000555

AC:

AN:

30628

American (AMR)

AF:

0.00

AC:

AN:

10502

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3519

South Asian (SAS)

AF:

0.00

AC:

AN:

2630

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6029

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53030

Other (OTH)

AF:

0.00

AC:

AN:

1487

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000151

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 01, 2017

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 21, 2016

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

ARHGEF9-related disorder

Benign:1

Jul 16, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Developmental and epileptic encephalopathy, 8

Benign:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

7.3

(source)

DANN

Benign

0.58

PhyloP100

3.0

Mutation Taster

=97/3

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over