X-63706406-T-C

Variant names:

• chrX-63706406-T-C
• rs377326713
• NM_001353921.2:c.254A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001353921.2(ARHGEF9):​c.254A>G​(p.Asp85Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000119 in 1,094,034 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D85N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000012 (0 hom. 8 hem.)
• Consequence: ARHGEF9 NM_001353921.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.67
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20101231).
• BS2: High Hemizygotes in GnomAdExome4 at 8 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.254A>G	p.Asp85Gly	missense	Exon 3 of 10	NP_001340850.1	A0A5F9ZHY9
	ARHGEF9	NM_001353923.1		c.272A>G	p.Asp91Gly	missense	Exon 3 of 10	NP_001340852.1	A0A1B0GWI5
	ARHGEF9	NM_001369030.1		c.233A>G	p.Asp78Gly	missense	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.254A>G	p.Asp85Gly	missense	Exon 3 of 10	ENSP00000500715.1	A0A5F9ZHY9
	ARHGEF9	ENST00000253401.10	TSL:1	c.233A>G	p.Asp78Gly	missense	Exon 3 of 10	ENSP00000253401.6	O43307-1
	ARHGEF9	ENST00000374878.5	TSL:1	c.254A>G	p.Asp85Gly	missense	Exon 3 of 10	ENSP00000364012.2	B1AMR4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.0000119 AC: 13 AN: 1094034 Hom.: 0 Cov.: 31 AF XY: 0.0000222 AC XY: 8 AN XY: 359992

African (AFR) AF: 0.00 AC: 0 AN: 26276

American (AMR) AF: 0.00 AC: 0 AN: 34997

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19295

East Asian (EAS) AF: 0.00 AC: 0 AN: 29939

South Asian (SAS) AF: 0.00 AC: 0 AN: 53133

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4075

European-Non Finnish (NFE) AF: 0.0000143 AC: 12 AN: 840338

Other (OTH) AF: 0.0000218 AC: 1 AN: 45953

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N
PhyloP100		5.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.056
Sift	Benign	0.47	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.28		Gain of glycosylation at S77 (P = 0.0293)
MVP		0.69
MPC		1.3
ClinPred		0.70	D
GERP RS		5.7
Varity_R		0.37
gMVP		0.82
Mutation Taster		=197/103	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: rs377326713; hg19: chrX-62926286;