chrX-63637846-CTGTG-C

Position:

• chrX-63637846-CTGTG-C

Variant summary

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

The NM_001353921.2(ARHGEF9):​c.*178_*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 0.0368 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
• 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-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/exons	MANE	UniProt
ARHGEF9	NM_001353921.2	c.*178_*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.*178_*181del		3_prime_UTR_variant	10/10		NM_001353921.2	A1

Frequencies

GnomAD3 genomes AF: 0.0563 AC: 5458 AN: 96864 Hom.: 277 Cov.: 12 AF XY: 0.0472 AC XY: 1117 AN XY: 23674

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.: 15 AF XY: 0.00655 AC XY: 378 AN XY: 57750

Gnomad4 AFR exome AF: 0.257

Gnomad4 AMR exome AF: 0.0269

Gnomad4 ASJ exome AF: 0.0195

Gnomad4 EAS exome AF: 0.0112

Gnomad4 SAS exome AF: 0.0227

Gnomad4 FIN exome AF: 0.0234

Gnomad4 NFE exome AF: 0.0197

Gnomad4 OTH exome AF: 0.0369

GnomAD4 genome AF: 0.0566 AC: 5482 AN: 96873 Hom.: 279 Cov.: 12 AF XY: 0.0478 AC XY: 1132 AN XY: 23693

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.0260

Gnomad4 ASJ AF: 0.0188

Gnomad4 EAS AF: 0.00383

Gnomad4 SAS AF: 0.0282

Gnomad4 FIN AF: 0.0150

Gnomad4 NFE AF: 0.0146

Gnomad4 OTH AF: 0.0384

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;