rs1556359038

Variant names:

• chrX-63674082-T-A
• rs1556359038
• NM_001353921.2:c.901A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001353921.2(ARHGEF9):​c.901A>T​(p.Ile301Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I301V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ARHGEF9 NM_001353921.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48
• 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_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001353921.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861

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.901A>T	p.Ile301Phe	missense	Exon 6 of 10	NP_001340850.1	A0A5F9ZHY9
	ARHGEF9	NM_001353923.1		c.919A>T	p.Ile307Phe	missense	Exon 6 of 10	NP_001340852.1	A0A1B0GWI5
	ARHGEF9	NM_001369030.1		c.880A>T	p.Ile294Phe	missense	Exon 7 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.901A>T	p.Ile301Phe	missense	Exon 6 of 10	ENSP00000500715.1	A0A5F9ZHY9
	ARHGEF9	ENST00000253401.10	TSL:1	c.880A>T	p.Ile294Phe	missense	Exon 6 of 10	ENSP00000253401.6	O43307-1
	ARHGEF9	ENST00000374878.5	TSL:1	c.901A>T	p.Ile301Phe	missense	Exon 6 of 10	ENSP00000364012.2	B1AMR4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.48		Loss of helix (P = 0.0626)
MVP		0.99
MPC		2.5
ClinPred		0.99	D
GERP RS		5.6
PromoterAI		-0.016	Neutral
Varity_R		0.79
gMVP		0.94
Mutation Taster		=6/94	disease causing

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: rs1556359038; hg19: chrX-62893962;