X-63638129-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001353921.2(ARHGEF9):c.1471G>A(p.Asp491Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000216 in 1,204,435 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D491E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.000011 ( 0 hom. 4 hem. )

Consequence

ARHGEF9
NM_001353921.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 5.68

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17155182).

BP6

Variant X-63638129-C-T is Benign according to our data. Variant chrX-63638129-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 383721.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF9	NM_001353921.2 link	c.1471G>A	p.Asp491Asn	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 link	c.1471G>A	p.Asp491Asn	missense_variant	Exon 10 of 10		NM_001353921.2	ENSP00000500715.1		A0A5F9ZHY9

Frequencies

GnomAD3 genomes

AF:

0.000126

AC:

AN:

110725

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00116

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000283

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000670

GnomAD2 exomes

AF:

0.0000175

AC:

AN:

171655

AF XY:

0.0000349

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:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000232

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1093710

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

359462

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26343

American (AMR)

AF:

0.0000862

AC:

AN:

34787

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19325

East Asian (EAS)

AF:

0.00

AC:

AN:

30061

South Asian (SAS)

AF:

0.00

AC:

AN:

53040

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40219

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.00000476

AC:

AN:

839869

Other (OTH)

AF:

0.000109

AC:

AN:

45935

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

0.000126

AC:

AN:

110725

Hom.:

Cov.:

AF XY:

0.0000910

AC XY:

AN XY:

32955

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30404

American (AMR)

AF:

0.00116

AC:

AN:

10314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2621

East Asian (EAS)

AF:

0.000283

AC:

AN:

3537

South Asian (SAS)

AF:

0.00

AC:

AN:

2576

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5894

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52966

Other (OTH)

AF:

0.000670

AC:

AN:

1493

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000868

Hom.:

Bravo

AF:

0.000223

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 27, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ARHGEF9 c.1450G>A (p.Asp484Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 171655 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1450G>A has been reported in the literature as a VUS in a male proband affected with West syndrome (Mitta_2020). This report does not provide unequivocal conclusions about association of the variant with Early Infantile Epileptic Encephalopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32593896). ClinVar contains an entry for this variant (Variation ID: 383721). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Jun 24, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1450G>A (p.D484N) alteration is located in coding exon 10 of the ARHGEF9 gene. This alteration results from a G to A substitution at nucleotide position 1450, causing the aspartic acid (D) at amino acid position 484 to be replaced by an asparagine (N). This alteration is rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the ARHGEF9 c.1450G>A alteration was observed in 4 among 188,266 total alleles studied (0.002%), having been observed in 3 total hemizygotes and 3/84,024 (0.004%) European (Non-Finnish) alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), this alteration was not observed among 6,503 total alleles studied. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project. Rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012; please note that some variants may appear to be rare due to ethnic underrepresentation in the database). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.D484 amino acid is conserved through available reptile species. The alteration is predicted benign by in silico models:_x000D_ _x000D_ The p.D484N alteration is predicted to be benign by Polyphen and tolerated by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Mar 27, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 8

Benign:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.084

T;.;T;T;T;T;T;T;.;T;.;T;T;.;T;.;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;.;D;.;.;.;D;.;D;.;.;D;.;D;D

M_CAP

Benign

0.056

MetaRNN

Benign

0.17

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.5

L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

5.7

PrimateAI

Uncertain

0.62

PROVEAN

Benign

0.61

N;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.

REVEL

Benign

0.18

Sift

Benign

0.17

T;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.

Sift4G

Benign

0.37

T;T;.;.;.;.;.;.;T;T;.;.;.;.;T;T;.

Polyphen

0.35

B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.25

MutPred

0.23

Gain of disorder (P = 0.2366);Gain of disorder (P = 0.2366);.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.81

MPC

1.0

ClinPred

0.14

GERP RS

5.5

Varity_R

0.21

gMVP

0.69

Mutation Taster

=42/58

disease causing

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over