chrX-63638198-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001353921.2(ARHGEF9):c.1402G>T(p.Ala468Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000355 in 1,181,827 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 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 Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A468V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000035 ( 0 hom. 11 hem. )

Consequence

ARHGEF9
NM_001353921.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.22

Publications

2 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030825675).

BP6

Variant X-63638198-C-A is Benign according to our data. Variant chrX-63638198-C-A is described in ClinVar as Benign. ClinVar VariationId is 567411.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 11 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.1402G>T	p.Ala468Ser	missense	Exon 10 of 10	NP_001340850.1
ARHGEF9	NM_001353923.1		c.1420G>T	p.Ala474Ser	missense	Exon 10 of 10	NP_001340852.1
ARHGEF9	NM_001369030.1		c.1381G>T	p.Ala461Ser	missense	Exon 11 of 11	NP_001355959.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARHGEF9	ENST00000671741.2	MANE Select	c.1402G>T	p.Ala468Ser	missense	Exon 10 of 10	ENSP00000500715.1
ARHGEF9	ENST00000253401.10	TSL:1	c.1381G>T	p.Ala461Ser	missense	Exon 10 of 10	ENSP00000253401.6
ARHGEF9	ENST00000624843.3	TSL:1	c.1075G>T	p.Ala359Ser	missense	Exon 9 of 9	ENSP00000485626.1

Frequencies

GnomAD3 genomes

AF:

0.0000456

AC:

AN:

109610

Hom.:

Cov.:

show subpopulations

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:

0.0000949

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000945

AC:

AN:

137609

AF XY:

0.0000942

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000691

Gnomad NFE exome

AF:

0.0000707

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000345

AC:

AN:

1072217

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

347931

show subpopulations

African (AFR)

AF:

0.0000387

AC:

AN:

25808

American (AMR)

AF:

0.00

AC:

AN:

31026

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18921

East Asian (EAS)

AF:

0.00

AC:

AN:

28924

South Asian (SAS)

AF:

0.0000196

AC:

AN:

51076

European-Finnish (FIN)

AF:

0.000462

AC:

AN:

39002

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4038

European-Non Finnish (NFE)

AF:

0.0000193

AC:

AN:

828246

Other (OTH)

AF:

0.0000221

AC:

AN:

45176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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:

0.0000456

AC:

AN:

109610

Hom.:

Cov.:

AF XY:

0.0000314

AC XY:

AN XY:

31884

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30032

American (AMR)

AF:

0.00

AC:

AN:

10174

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2610

East Asian (EAS)

AF:

0.00

AC:

AN:

3466

South Asian (SAS)

AF:

0.00

AC:

AN:

2522

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5733

Middle Eastern (MID)

AF:

0.00

AC:

AN:

233

European-Non Finnish (NFE)

AF:

0.0000949

AC:

AN:

52694

Other (OTH)

AF:

0.00

AC:

AN:

1468

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000513

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 8

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.079

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.81

M_CAP

Benign

0.011

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.1

PhyloP100

2.2

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.090

REVEL

Benign

0.11

Sift

Benign

0.84

Sift4G

Benign

0.59

Polyphen

0.0

Vest4

0.055

MutPred

0.27

Gain of glycosylation at A461 (P = 0.0107)

MVP

0.59

MPC

0.92

ClinPred

0.11

GERP RS

4.5

Varity_R

0.12

gMVP

0.61

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over