rs373866956

Variant names:

• chrX-63706309-C-T
• rs373866956
• NM_001353921.2:c.351G>A
• ARHGEF9 p.Glu117Glu

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_001353921.2(ARHGEF9):​c.351G>A​(p.Glu117Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000382 in 1,204,439 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000037 (0 hom. 7 hem.)
• Consequence: ARHGEF9 NM_001353921.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.523
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 8

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant X-63706309-C-T is Benign according to our data. Variant chrX-63706309-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 465080.
• BP7: Synonymous conserved (PhyloP=0.523 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 7 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353921.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF9	NM_001353921.2	MANE Select	c.351G>A	p.Glu117Glu	synonymous	Exon 3 of 10	NP_001340850.1	A0A5F9ZHY9
	ARHGEF9	NM_001353923.1		c.369G>A	p.Glu123Glu	synonymous	Exon 3 of 10	NP_001340852.1	A0A1B0GWI5
	ARHGEF9	NM_001369030.1		c.330G>A	p.Glu110Glu	synonymous	Exon 4 of 11	NP_001355959.1	O43307-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF9	ENST00000671741.2	MANE Select	c.351G>A	p.Glu117Glu	synonymous	Exon 3 of 10	ENSP00000500715.1	A0A5F9ZHY9
	ARHGEF9	ENST00000253401.10	TSL:1	c.330G>A	p.Glu110Glu	synonymous	Exon 3 of 10	ENSP00000253401.6	O43307-1
	ARHGEF9	ENST00000374878.5	TSL:1	c.351G>A	p.Glu117Glu	synonymous	Exon 3 of 10	ENSP00000364012.2	B1AMR4

Frequencies

GnomAD3 genomes AF: 0.0000541 AC: 6 AN: 110954 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000955

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00114

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000673

GnomAD2 exomes AF: 0.0000645 AC: 11 AN: 170463 AF XY: 0.0000353

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000752

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000366 AC: 40 AN: 1093485 Hom.: 0 Cov.: 31 AF XY: 0.0000195 AC XY: 7 AN XY: 359523

African (AFR) AF: 0.00 AC: 0 AN: 26337

American (AMR) AF: 0.00 AC: 0 AN: 34861

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19277

East Asian (EAS) AF: 0.000566 AC: 17 AN: 30040

South Asian (SAS) AF: 0.00 AC: 0 AN: 53085

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40211

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00000357 AC: 3 AN: 839632

Other (OTH) AF: 0.000436 AC: 20 AN: 45914

GnomAD4 genome AF: 0.0000541 AC: 6 AN: 110954 Hom.: 0 Cov.: 22 AF XY: 0.0000302 AC XY: 1 AN XY: 33118

African (AFR) AF: 0.00 AC: 0 AN: 30450

American (AMR) AF: 0.0000955 AC: 1 AN: 10471

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00114 AC: 4 AN: 3513

South Asian (SAS) AF: 0.00 AC: 0 AN: 2537

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5919

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53009

Other (OTH) AF: 0.000673 AC: 1 AN: 1485

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 8 (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.7
DANN	Benign	0.56
PhyloP100		0.52
Mutation Taster		=94/6	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs373866956;

hg19: chrX-62926189;