X-63637882-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001353921.2(ARHGEF9):c.*146G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., 31 hem., cov: 19)
  • Exomes 𝑓: 0.0041 (1 hom. 83 hem.)
• Consequence: ARHGEF9 NM_001353921.2 3_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.569

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant X-63637882-C-G is Benign according to our data. Variant chrX-63637882-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 633481.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00286 (240/83962) while in subpopulation AFR AF= 0.0102 (220/21601). AF 95% confidence interval is 0.00908. There are 1 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 19. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 31 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF9	NM_001353921.2	c.*146G>C		3_prime_UTR_variant	10/10	ENST00000671741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF9	ENST00000671741.2	c.*146G>C		3_prime_UTR_variant	10/10		NM_001353921.2	A1

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 240 AN: 83959 Hom.: 1 Cov.: 19 AF XY: 0.00145 AC XY: 31 AN XY: 21325

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000824

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000510

Gnomad FIN AF: 0.000763

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000211

Gnomad OTH AF: 0.000923

GnomAD4 exome AF: 0.00414 AC: 842 AN: 203368 Hom.: 1 Cov.: 4 AF XY: 0.00140 AC XY: 83 AN XY: 59356

Gnomad4 AFR exome AF: 0.00495

Gnomad4 AMR exome AF: 0.00969

Gnomad4 ASJ exome AF: 0.00415

Gnomad4 EAS exome AF: 0.00397

Gnomad4 SAS exome AF: 0.00242

Gnomad4 FIN exome AF: 0.00538

Gnomad4 NFE exome AF: 0.00370

Gnomad4 OTH exome AF: 0.00480

GnomAD4 genome AF: 0.00286 AC: 240 AN: 83962 Hom.: 1 Cov.: 19 AF XY: 0.00145 AC XY: 31 AN XY: 21342

Gnomad4 AFR AF: 0.0102

Gnomad4 AMR AF: 0.000823

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000513

Gnomad4 FIN AF: 0.000763

Gnomad4 NFE AF: 0.000211

Gnomad4 OTH AF: 0.000913

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Epilepsy Benign:1

Likely benign, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Jul 26, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.025
Dann	Benign	0.39

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: rs782358245; hg19: chrX-62857762;