rs371200226

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4BP6_Very_StrongBS2

The NM_001353921.2(ARHGEF9):c.1490A>G(p.Gln497Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 1,207,291 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 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 0.000027 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000028 ( 0 hom. 11 hem. )

Consequence

ARHGEF9
NM_001353921.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.48

Publications

3 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: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
X-linked complex neurodevelopmental disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ARHGEF9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32513314).

BP6

Variant X-63638110-T-C is Benign according to our data. Variant chrX-63638110-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1161327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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	UniProt
ARHGEF9	NM_001353921.2	MANE Select	c.1490A>G	p.Gln497Arg	missense	Exon 10 of 10	NP_001340850.1	A0A5F9ZHY9
ARHGEF9	NM_001353923.1		c.1508A>G	p.Gln503Arg	missense	Exon 10 of 10	NP_001340852.1	A0A1B0GWI5
ARHGEF9	NM_001369030.1		c.1469A>G	p.Gln490Arg	missense	Exon 11 of 11	NP_001355959.1	O43307-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGEF9	ENST00000671741.2	MANE Select	c.1490A>G	p.Gln497Arg	missense	Exon 10 of 10	ENSP00000500715.1	A0A5F9ZHY9
ARHGEF9	ENST00000253401.10	TSL:1	c.1469A>G	p.Gln490Arg	missense	Exon 10 of 10	ENSP00000253401.6	O43307-1
ARHGEF9	ENST00000624843.3	TSL:1	c.1163A>G	p.Gln388Arg	missense	Exon 9 of 9	ENSP00000485626.1	O43307-3

Frequencies

GnomAD3 genomes

AF:

0.0000270

AC:

AN:

111283

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:

0.0000565

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000451

AC:

AN:

177332

AF XY:

0.0000482

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:

0.000102

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000283

AC:

AN:

1096008

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

361458

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26391

American (AMR)

AF:

0.00

AC:

AN:

35046

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19356

East Asian (EAS)

AF:

0.00

AC:

AN:

30140

South Asian (SAS)

AF:

0.00

AC:

AN:

53457

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40373

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.0000369

AC:

AN:

841095

Other (OTH)

AF:

0.00

AC:

AN:

46020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

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:

0.0000270

AC:

AN:

111283

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33469

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30540

American (AMR)

AF:

0.00

AC:

AN:

10404

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2638

East Asian (EAS)

AF:

0.00

AC:

AN:

3559

South Asian (SAS)

AF:

0.00

AC:

AN:

2615

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6010

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000565

AC:

AN:

53086

Other (OTH)

AF:

0.00

AC:

AN:

1509

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0953088), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

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:

0.00

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 8 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.048

MetaRNN

Benign

0.33

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.2

PhyloP100

7.5

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.31

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0060

Polyphen

0.47

Vest4

0.17

MVP

0.92

MPC

1.3

ClinPred

0.35

GERP RS

5.3

Varity_R

0.61

gMVP

0.82

Mutation Taster

=85/15

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over