Genetic Variant ARHGEF9:c.*178_*181delCACA (chrX-63637846-CTGTG-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_001353921.2(ARHGEF9):c.*178_*181delCACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0368 in 297,765 control chromosomes in the GnomAD database, including 294 homozygotes. There are 1,510 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.057 ( 279 hom., 1132 hem., cov: 12)

Exomes 𝑓: 0.027 ( 15 hom. 378 hem. )

Consequence

ARHGEF9
NM_001353921.2 3_prime_UTR

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.87

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant X-63637846-CTGTG-C is Benign according to our data. Variant chrX-63637846-CTGTG-C is described in ClinVar as [Benign]. Clinvar id is 1276283.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF9	NM_001353921.2 link	c.178_181delCACA		3_prime_UTR_variant	Exon 10 of 10	ENST00000671741.2	NP_001340850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF9	ENST00000671741 link	c.178_181delCACA		3_prime_UTR_variant	Exon 10 of 10		NM_001353921.2	ENSP00000500715.1		A0A5F9ZHY9

Frequencies

GnomAD3 genomes

AF:

0.0563

AC:

5458

AN:

96864

Hom.:

277

Cov.:

show subpopulations

Gnomad AFR

AF:

0.167

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0261

Gnomad ASJ

AF:

0.0188

Gnomad EAS

AF:

0.00382

Gnomad SAS

AF:

0.0275

Gnomad FIN

AF:

0.0150

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0146

Gnomad OTH

AF:

0.0390

GnomAD4 exome

AF:

0.0273

AC:

5483

AN:

200892

Hom.:

AF XY:

0.00655

AC XY:

378

AN XY:

57750

show subpopulations

Gnomad4 AFR exome

AF:

0.257

AC:

1429

AN:

5567

Gnomad4 AMR exome

AF:

0.0269

AC:

210

AN:

7797

Gnomad4 ASJ exome

AF:

0.0195

AC:

126

AN:

6470

Gnomad4 EAS exome

AF:

0.0112

AC:

183

AN:

16282

Gnomad4 SAS exome

AF:

0.0227

AC:

163

AN:

7172

Gnomad4 FIN exome

AF:

0.0234

AC:

328

AN:

14025

Gnomad4 NFE exome

AF:

0.0197

AC:

2565

AN:

130158

Gnomad4 Remaining exome

AF:

0.0369

AC:

463

AN:

12545

Heterozygous variant carriers

246

492

737

983

1229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.0566

AC:

5482

AN:

96873

Hom.:

279

Cov.:

AF XY:

0.0478

AC XY:

1132

AN XY:

23693

show subpopulations

Gnomad4 AFR

AF:

0.168

AC:

0.168049

AN:

0.168049

Gnomad4 AMR

AF:

0.0260

AC:

0.0260363

AN:

0.0260363

Gnomad4 ASJ

AF:

0.0188

AC:

0.0188285

AN:

0.0188285

Gnomad4 EAS

AF:

0.00383

AC:

0.00383387

AN:

0.00383387

Gnomad4 SAS

AF:

0.0282

AC:

0.0282432

AN:

0.0282432

Gnomad4 FIN

AF:

0.0150

AC:

0.0149902

AN:

0.0149902

Gnomad4 NFE

AF:

0.0146

AC:

0.0146175

AN:

0.0146175

Gnomad4 OTH

AF:

0.0384

AC:

0.038432

AN:

0.038432

Heterozygous variant carriers

178

357

535

714

892

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.00414

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 10, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=100/0

polymorphism (auto)

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over