X-63637846-C-CTG

Variant summary

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

The NM_001353921.2(ARHGEF9):c.*181_*182insCA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.047 (120 hom., 806 hem., cov: 12)
  • Exomes 𝑓: 0.033 (5 hom. 159 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-C-CTG is Benign according to our data. Variant chrX-63637846-C-CTG is described in ClinVar as [Benign]. Clinvar id is 1249525.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF9	NM_001353921.2	c.*181_*182insCA		3_prime_UTR_variant	10/10	ENST00000671741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF9	ENST00000671741.2	c.*181_*182insCA		3_prime_UTR_variant	10/10		NM_001353921.2	A1

Frequencies

GnomAD3 genomes AF: 0.0472 AC: 4576 AN: 96937 Hom.: 122 Cov.: 12 AF XY: 0.0340 AC XY: 807 AN XY: 23709

Gnomad AFR AF: 0.0217

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.0480

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.0325

Gnomad SAS AF: 0.0256

Gnomad FIN AF: 0.0411

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.0581

Gnomad OTH AF: 0.0685

GnomAD4 exome AF: 0.0333 AC: 6906 AN: 207305 Hom.: 5 Cov.: 0 AF XY: 0.00270 AC XY: 159 AN XY: 58931

Gnomad4 AFR exome AF: 0.0121

Gnomad4 AMR exome AF: 0.0288

Gnomad4 ASJ exome AF: 0.0705

Gnomad4 EAS exome AF: 0.0163

Gnomad4 SAS exome AF: 0.0172

Gnomad4 FIN exome AF: 0.0368

Gnomad4 NFE exome AF: 0.0347

Gnomad4 OTH exome AF: 0.0393

GnomAD4 genome AF: 0.0471 AC: 4569 AN: 96949 Hom.: 120 Cov.: 12 AF XY: 0.0340 AC XY: 806 AN XY: 23731

Gnomad4 AFR AF: 0.0218

Gnomad4 AMR AF: 0.0480

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.0320

Gnomad4 SAS AF: 0.0254

Gnomad4 FIN AF: 0.0411

Gnomad4 NFE AF: 0.0581

Gnomad4 OTH AF: 0.0691

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

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Computational scores

Source: dbNSFP v4.3

Splicing

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;