Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001353921.2(ARHGEF9):c.4C>T(p.Gln2*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

ARHGEF9
NM_001353921.2 stop_gained

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.57

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

ARHGEF9 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 42 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-63785142-G-A is Pathogenic according to our data. Variant chrX-63785142-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 29968.Status of the report is no_assertion_criteria_provided, 0 stars.

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.4C>T	p.Gln2*	stop_gained	Exon 1 of 10	NP_001340850.1
ARHGEF9	NM_001353922.2		c.4C>T	p.Gln2*	stop_gained	Exon 1 of 9	NP_001340851.1
ARHGEF9	NM_001173479.2		c.4C>T	p.Gln2*	stop_gained	Exon 1 of 9	NP_001166950.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARHGEF9	ENST00000671741.2	MANE Select	c.4C>T	p.Gln2*	stop_gained	Exon 1 of 10	ENSP00000500715.1
ARHGEF9	ENST00000374878.5	TSL:1	c.4C>T	p.Gln2*	stop_gained	Exon 1 of 10	ENSP00000364012.2
ARHGEF9	ENST00000437457.6	TSL:5	c.4C>T	p.Gln2*	stop_gained	Exon 1 of 11	ENSP00000399994.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1051601

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

343165

African (AFR)

AF:

0.00

AC:

AN:

24874

American (AMR)

AF:

0.00

AC:

AN:

27835

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18587

East Asian (EAS)

AF:

0.00

AC:

AN:

27059

South Asian (SAS)

AF:

0.00

AC:

AN:

49660

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36772

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4079

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

818452

Other (OTH)

AF:

0.00

AC:

AN:

44283

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 8 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Benign

0.57

PhyloP100

3.6

Vest4

0.61

GERP RS

4.4

PromoterAI

0.0060

Neutral

(source)

Mutation Taster

=19/181

disease causing (ClinVar)

(source)

Splicing

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

Publications

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rs397514460

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over