X-63638198-C-T

Variant names:

• chrX-63638198-C-T
• rs781870482
• NM_001353921.2:c.1402G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001353921.2(ARHGEF9):​c.1402G>A​(p.Ala468Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000933 in 1,072,220 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. 15/21 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. A468V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.3e-7 (0 hom. 1 hem.)
• Consequence: ARHGEF9 NM_001353921.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.22
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.081581354).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF9	NM_001353921.2	MANE Select	c.1402G>A	p.Ala468Thr	missense	Exon 10 of 10	NP_001340850.1
	ARHGEF9	NM_001353923.1		c.1420G>A	p.Ala474Thr	missense	Exon 10 of 10	NP_001340852.1
	ARHGEF9	NM_001369030.1		c.1381G>A	p.Ala461Thr	missense	Exon 11 of 11	NP_001355959.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF9	ENST00000671741.2	MANE Select	c.1402G>A	p.Ala468Thr	missense	Exon 10 of 10	ENSP00000500715.1
	ARHGEF9	ENST00000253401.10	TSL:1	c.1381G>A	p.Ala461Thr	missense	Exon 10 of 10	ENSP00000253401.6
	ARHGEF9	ENST00000624843.3	TSL:1	c.1075G>A	p.Ala359Thr	missense	Exon 9 of 9	ENSP00000485626.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.33e-7 AC: 1 AN: 1072220 Hom.: 0 Cov.: 30 AF XY: 0.00000287 AC XY: 1 AN XY: 347934

African (AFR) AF: 0.00 AC: 0 AN: 25808

American (AMR) AF: 0.00 AC: 0 AN: 31026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18921

East Asian (EAS) AF: 0.00 AC: 0 AN: 28924

South Asian (SAS) AF: 0.00 AC: 0 AN: 51076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4038

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 828249

Other (OTH) AF: 0.00 AC: 0 AN: 45176

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.13	T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.34	N
PhyloP100		2.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.082
Sift	Benign	0.36	T
Sift4G	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.038
MutPred		0.20		Gain of glycosylation at A461 (P = 0.0115)
MVP		0.72
MPC		0.97
ClinPred		0.37	T
GERP RS		4.5
Varity_R		0.13
gMVP		0.66
Mutation Taster		=82/18	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: rs781870482; hg19: chrX-62858078;