rs140777637

Variant names:

• chrX-63678480-C-T
• rs140777637
• NM_001353921.2:c.675G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001353921.2(ARHGEF9):​c.675G>A​(p.Gln225Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 1,202,473 control chromosomes in the GnomAD database, including 1 homozygotes. There are 173 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 0.00038 (0 hom., 11 hem., cov: 23)
  • Exomes 𝑓: 0.00041 (1 hom. 162 hem.)
• Consequence: ARHGEF9 NM_001353921.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 2.95
• Publications: 0 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), Orphanet, Ambry Genetics, G2P
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant X-63678480-C-T is Benign according to our data. Variant chrX-63678480-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128451.
• BP7: Synonymous conserved (PhyloP=2.95 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 11 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.675G>A	p.Gln225Gln	synonymous	Exon 5 of 10	NP_001340850.1	A0A5F9ZHY9
	ARHGEF9	NM_001353923.1		c.693G>A	p.Gln231Gln	synonymous	Exon 5 of 10	NP_001340852.1	A0A1B0GWI5
	ARHGEF9	NM_001369030.1		c.654G>A	p.Gln218Gln	synonymous	Exon 6 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.675G>A	p.Gln225Gln	synonymous	Exon 5 of 10	ENSP00000500715.1	A0A5F9ZHY9
	ARHGEF9	ENST00000253401.10	TSL:1	c.654G>A	p.Gln218Gln	synonymous	Exon 5 of 10	ENSP00000253401.6	O43307-1
	ARHGEF9	ENST00000374878.5	TSL:1	c.675G>A	p.Gln225Gln	synonymous	Exon 5 of 10	ENSP00000364012.2	B1AMR4

Frequencies

GnomAD3 genomes AF: 0.000377 AC: 42 AN: 111391 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000956

Gnomad ASJ AF: 0.00416

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.000527

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000459 AC: 77 AN: 167935 AF XY: 0.000584

Gnomad AFR exome AF: 0.0000827

Gnomad AMR exome AF: 0.000114

Gnomad ASJ exome AF: 0.00348

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000424

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.000413 AC: 451 AN: 1091032 Hom.: 1 Cov.: 30 AF XY: 0.000453 AC XY: 162 AN XY: 357448

African (AFR) AF: 0.000304 AC: 8 AN: 26339

American (AMR) AF: 0.000173 AC: 6 AN: 34636

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 72 AN: 19221

East Asian (EAS) AF: 0.00 AC: 0 AN: 30049

South Asian (SAS) AF: 0.000512 AC: 27 AN: 52742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39989

Middle Eastern (MID) AF: 0.00606 AC: 25 AN: 4123

European-Non Finnish (NFE) AF: 0.000329 AC: 276 AN: 838130

Other (OTH) AF: 0.000808 AC: 37 AN: 45803

GnomAD4 genome AF: 0.000377 AC: 42 AN: 111441 Hom.: 0 Cov.: 23 AF XY: 0.000327 AC XY: 11 AN XY: 33627

African (AFR) AF: 0.0000326 AC: 1 AN: 30693

American (AMR) AF: 0.0000955 AC: 1 AN: 10472

Ashkenazi Jewish (ASJ) AF: 0.00416 AC: 11 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3525

South Asian (SAS) AF: 0.00 AC: 0 AN: 2589

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5982

Middle Eastern (MID) AF: 0.00459 AC: 1 AN: 218

European-Non Finnish (NFE) AF: 0.000527 AC: 28 AN: 53127

Other (OTH) AF: 0.00 AC: 0 AN: 1506

Alfa AF: 0.00135 Hom.: 8

Bravo AF: 0.000385

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	ARHGEF9-related disorder (1)
-	-	1	Developmental and epileptic encephalopathy, 8 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.4
DANN	Benign	0.74
PhyloP100		3.0
Mutation Taster		=98/2	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

Other links and lift over

dbSNP: rs140777637; hg19: chrX-62898360;