chrX-63637846-CTG-C

Position:

• chrX-63637846-CTG-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001353921.2(ARHGEF9):​c.*180_*181del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 259,948 control chromosomes in the GnomAD database, including 3,521 homozygotes. There are 3,676 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (3446 hom., 3128 hem., cov: 12)
  • Exomes 𝑓: 0.22 (75 hom. 548 hem.)
• Consequence: ARHGEF9 NM_001353921.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.87

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant X-63637846-CTG-C is Benign according to our data. Variant chrX-63637846-CTG-C is described in ClinVar as [Benign]. Clinvar id is 1247816.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF9	NM_001353921.2	c.*180_*181del		3_prime_UTR_variant	10/10	ENST00000671741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF9	ENST00000671741.2	c.*180_*181del		3_prime_UTR_variant	10/10		NM_001353921.2	A1

Frequencies

GnomAD3 genomes AF: 0.177 AC: 17091 AN: 96514 Hom.: 3448 Cov.: 12 AF XY: 0.133 AC XY: 3122 AN XY: 23554

Gnomad AFR AF: 0.570

Gnomad AMI AF: 0.0313

Gnomad AMR AF: 0.0698

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.0339

Gnomad SAS AF: 0.0152

Gnomad FIN AF: 0.0272

Gnomad MID AF: 0.0293

Gnomad NFE AF: 0.0290

Gnomad OTH AF: 0.129

GnomAD4 exome AF: 0.223 AC: 36423 AN: 163425 Hom.: 75 AF XY: 0.0174 AC XY: 548 AN XY: 31413

Gnomad4 AFR exome AF: 0.402

Gnomad4 AMR exome AF: 0.247

Gnomad4 ASJ exome AF: 0.203

Gnomad4 EAS exome AF: 0.260

Gnomad4 SAS exome AF: 0.160

Gnomad4 FIN exome AF: 0.228

Gnomad4 NFE exome AF: 0.209

Gnomad4 OTH exome AF: 0.242

GnomAD4 genome AF: 0.177 AC: 17098 AN: 96523 Hom.: 3446 Cov.: 12 AF XY: 0.133 AC XY: 3128 AN XY: 23573

Gnomad4 AFR AF: 0.569

Gnomad4 AMR AF: 0.0697

Gnomad4 ASJ AF: 0.0231

Gnomad4 EAS AF: 0.0336

Gnomad4 SAS AF: 0.0148

Gnomad4 FIN AF: 0.0272

Gnomad4 NFE AF: 0.0290

Gnomad4 OTH AF: 0.128

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs10542660; hg19: chrX-62857726;