Genetic Variant ARHGEF9:c.*168_*181delCACACACACACACA (chrX-63637846-CTGTGTGTGTGTGTG-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001353921.2(ARHGEF9):c.*168_*181delCACACACACACACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000386 in 310,520 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000021 ( 0 hom., 1 hem., cov: 12)

Exomes 𝑓: 0.000047 ( 0 hom. 4 hem. )

Consequence

ARHGEF9
NM_001353921.2 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.56

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 4 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	Effect	Exon Rank	Protein	UniProt
ARHGEF9	NM_001353921.2	MANE Select	c.168_181delCACACACACACACA	3_prime_UTR	Exon 10 of 10	NP_001340850.1	A0A5F9ZHY9
ARHGEF9	NM_001353923.1		c.168_181delCACACACACACACA	3_prime_UTR	Exon 10 of 10	NP_001340852.1	A0A1B0GWI5
ARHGEF9	NM_001369030.1		c.168_181delCACACACACACACA	3_prime_UTR	Exon 11 of 11	NP_001355959.1	O43307-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ARHGEF9	ENST00000671741.2	MANE Select	c.168_181delCACACACACACACA	3_prime_UTR	Exon 10 of 10	ENSP00000500715.1	A0A5F9ZHY9
ARHGEF9	ENST00000253401.10	TSL:1	c.168_181delCACACACACACACA	3_prime_UTR	Exon 10 of 10	ENSP00000253401.6	O43307-1
ARHGEF9	ENST00000374878.5	TSL:1	c.1375-2452_1375-2439delCACACACACACACA	intron	N/A	ENSP00000364012.2	B1AMR4

Frequencies

GnomAD3 genomes

AF:

0.0000309

AC:

AN:

97025

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000777

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000318

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000468

AC:

AN:

213481

Hom.:

AF XY:

0.0000628

AC XY:

AN XY:

63651

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

6675

American (AMR)

AF:

0.00

AC:

AN:

8273

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6829

East Asian (EAS)

AF:

0.000405

AC:

AN:

17304

South Asian (SAS)

AF:

0.000132

AC:

AN:

7595

European-Finnish (FIN)

AF:

0.00

AC:

AN:

14833

Middle Eastern (MID)

AF:

0.00

AC:

AN:

917

European-Non Finnish (NFE)

AF:

0.0000145

AC:

AN:

137716

Other (OTH)

AF:

0.00

AC:

AN:

13339

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:

0.0000206

AC:

AN:

97039

Hom.:

Cov.:

AF XY:

0.0000420

AC XY:

AN XY:

23789

show subpopulations

African (AFR)

AF:

0.0000776

AC:

AN:

25781

American (AMR)

AF:

0.00

AC:

AN:

8768

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2390

East Asian (EAS)

AF:

0.00

AC:

AN:

3131

South Asian (SAS)

AF:

0.00

AC:

AN:

2090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

186

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

48125

Other (OTH)

AF:

0.00

AC:

AN:

1305

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.6

Splicing

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

Publications

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X-63637846-CTGTGTGTGTGTGTGTGTGTGTGTG-CTGTGTGTGTG

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