chrX-63706406-T-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001173480.2(ARHGEF9):c.-74A>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000332 in 1,205,515 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000018 ( 0 hom. 2 hem. )

Consequence

ARHGEF9
NM_001173480.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.67

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16598889).

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001173480.2. 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.254A>T	p.Asp85Val	missense	Exon 3 of 10	NP_001340850.1
ARHGEF9	NM_001173480.2		c.-74A>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	NP_001166951.1
ARHGEF9	NM_001369042.1		c.-74A>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 11	NP_001355971.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARHGEF9	ENST00000624843.3	TSL:1	c.-74A>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	ENSP00000485626.1
ARHGEF9	ENST00000671741.2	MANE Select	c.254A>T	p.Asp85Val	missense	Exon 3 of 10	ENSP00000500715.1
ARHGEF9	ENST00000253401.10	TSL:1	c.233A>T	p.Asp78Val	missense	Exon 3 of 10	ENSP00000253401.6

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111481

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:

0.0000377

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000581

AC:

AN:

172005

AF XY:

0.00

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:

0.0000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000183

AC:

AN:

1094034

Hom.:

Cov.:

AF XY:

0.00000556

AC XY:

AN XY:

359992

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26276

American (AMR)

AF:

0.00

AC:

AN:

34997

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19295

East Asian (EAS)

AF:

0.00

AC:

AN:

29939

South Asian (SAS)

AF:

0.00

AC:

AN:

53133

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40028

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4075

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

840338

Other (OTH)

AF:

0.00

AC:

AN:

45953

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111481

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33653

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30611

American (AMR)

AF:

0.00

AC:

AN:

10563

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3535

South Asian (SAS)

AF:

0.00

AC:

AN:

2605

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6011

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000377

AC:

AN:

53082

Other (OTH)

AF:

0.00

AC:

AN:

1504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 8 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.87

MutationAssessor

Benign

-0.34

PhyloP100

5.7

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.3

REVEL

Benign

0.087

Sift

Benign

0.13

Sift4G

Benign

0.18

Polyphen

0.021

Vest4

0.28

MVP

0.79

MPC

1.4

ClinPred

0.52

GERP RS

5.7

Varity_R

0.45

gMVP

0.83

Mutation Taster

=197/103

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over