NM_001353921.2:c.939C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_001353921.2(ARHGEF9):c.939C>G(p.Asp313Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000485 in 1,209,430 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 190 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D313D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., 7 hem., cov: 23)

Exomes 𝑓: 0.00051 ( 0 hom. 183 hem. )

Consequence

ARHGEF9
NM_001353921.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.60

Publications

4 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11057103).

BP6

Variant X-63674044-G-C is Benign according to our data. Variant chrX-63674044-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 383604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 7 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.939C>G	p.Asp313Glu	missense	Exon 6 of 10	NP_001340850.1	A0A5F9ZHY9
ARHGEF9	NM_001353923.1		c.957C>G	p.Asp319Glu	missense	Exon 6 of 10	NP_001340852.1	A0A1B0GWI5
ARHGEF9	NM_001369030.1		c.918C>G	p.Asp306Glu	missense	Exon 7 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.939C>G	p.Asp313Glu	missense	Exon 6 of 10	ENSP00000500715.1	A0A5F9ZHY9
ARHGEF9	ENST00000253401.10	TSL:1	c.918C>G	p.Asp306Glu	missense	Exon 6 of 10	ENSP00000253401.6	O43307-1
ARHGEF9	ENST00000374878.5	TSL:1	c.939C>G	p.Asp313Glu	missense	Exon 6 of 10	ENSP00000364012.2	B1AMR4

Frequencies

GnomAD3 genomes

AF:

0.000241

AC:

AN:

111902

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:

0.000508

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000350

AC:

AN:

182813

AF XY:

0.000297

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000267

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000631

Gnomad NFE exome

AF:

0.000724

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000509

AC:

559

AN:

1097475

Hom.:

Cov.:

AF XY:

0.000504

AC XY:

183

AN XY:

363085

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

26375

American (AMR)

AF:

0.00

AC:

AN:

35187

Ashkenazi Jewish (ASJ)

AF:

0.000103

AC:

AN:

19357

East Asian (EAS)

AF:

0.00

AC:

AN:

30193

South Asian (SAS)

AF:

0.00

AC:

AN:

54132

European-Finnish (FIN)

AF:

0.0000247

AC:

AN:

40421

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4100

European-Non Finnish (NFE)

AF:

0.000640

AC:

539

AN:

841648

Other (OTH)

AF:

0.000282

AC:

AN:

46062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.000241

AC:

AN:

111955

Hom.:

Cov.:

AF XY:

0.000205

AC XY:

AN XY:

34137

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30785

American (AMR)

AF:

0.00

AC:

AN:

10588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3558

South Asian (SAS)

AF:

0.00

AC:

AN:

2674

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6092

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.000508

AC:

AN:

53192

Other (OTH)

AF:

0.00

AC:

AN:

1522

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

Genome 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

Alfa

AF:

0.000531

Hom.:

Bravo

AF:

0.000302

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000743

AC:

ExAC

AF:

0.000264

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000653

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

ARHGEF9-related disorder (1)

Developmental and epileptic encephalopathy, 8 (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.79

M_CAP

Benign

0.052

MetaRNN

Benign

0.11

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.8

PhyloP100

2.6

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.32

Sift

Benign

0.080

Sift4G

Benign

0.081

Polyphen

0.38

Vest4

0.26

MutPred

0.49

Gain of helix (P = 0.0696)

MVP

0.91

MPC

0.98

ClinPred

0.045

GERP RS

2.9

PromoterAI

-0.025

Neutral

(source)

Varity_R

0.36

gMVP

0.82

Mutation Taster

=86/14

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over