X-63785142-G-T

Variant names:

• chrX-63785142-G-T
• rs397514460
• NM_001353921.2:c.4C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001353921.2(ARHGEF9):​c.4C>A​(p.Gln2Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000258 in 1,163,451 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict 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. Q2R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.0000019 (0 hom. 0 hem.)
• Consequence: ARHGEF9 NM_001353921.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.57
• Publications: 4 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3764873).

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.4C>A	p.Gln2Lys	missense	Exon 1 of 10	NP_001340850.1	A0A5F9ZHY9
	ARHGEF9	NM_001353922.2		c.4C>A	p.Gln2Lys	missense	Exon 1 of 9	NP_001340851.1
	ARHGEF9	NM_001173479.2		c.4C>A	p.Gln2Lys	missense	Exon 1 of 9	NP_001166950.1	O43307-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF9	ENST00000671741.2	MANE Select	c.4C>A	p.Gln2Lys	missense	Exon 1 of 10	ENSP00000500715.1	A0A5F9ZHY9
	ARHGEF9	ENST00000374878.5	TSL:1	c.4C>A	p.Gln2Lys	missense	Exon 1 of 10	ENSP00000364012.2	B1AMR4
	ARHGEF9	ENST00000922913.1		c.4C>A	p.Gln2Lys	missense	Exon 1 of 10	ENSP00000592972.1

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111850 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000190 AC: 2 AN: 1051601 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 343165

African (AFR) AF: 0.00 AC: 0 AN: 24874

American (AMR) AF: 0.00 AC: 0 AN: 27835

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18587

East Asian (EAS) AF: 0.00 AC: 0 AN: 27059

South Asian (SAS) AF: 0.00 AC: 0 AN: 49660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4079

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 818452

Other (OTH) AF: 0.0000226 AC: 1 AN: 44283

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111850 Hom.: 0 Cov.: 22 AF XY: 0.0000294 AC XY: 1 AN XY: 34020

African (AFR) AF: 0.00 AC: 0 AN: 30742

American (AMR) AF: 0.00 AC: 0 AN: 10615

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3519

South Asian (SAS) AF: 0.00 AC: 0 AN: 2660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53096

Other (OTH) AF: 0.00 AC: 0 AN: 1505

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0073	T
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.83	T
PhyloP100		3.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.066
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.16	T
Vest4		0.35
MutPred		0.34		Gain of catalytic residue at Q2 (P = 0.0082)
MVP		0.85
ClinPred		0.66	D
GERP RS		4.4
PromoterAI		0.11	Neutral
Mutation Taster		=289/11	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397514460; hg19: chrX-63005022;