rs189661969

Variant names:

• chrX-63635344-T-C
• rs189661969
• ENST00000374878.5:c.1439A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000374878.5(ARHGEF9):​c.1439A>G​(p.Asn480Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000596 in 520,387 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., 3 hem., cov: 22)
  • Exomes 𝑓: 0.000037 (0 hom. 4 hem.)
• Consequence: ARHGEF9 ENST00000374878.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.737
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00903374).
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000374878.5. 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.*2684A>G		3_prime_UTR	Exon 10 of 10	NP_001340850.1	A0A5F9ZHY9
	ARHGEF9	NM_001353923.1		c.*2684A>G		3_prime_UTR	Exon 10 of 10	NP_001340852.1	A0A1B0GWI5
	ARHGEF9	NM_001369030.1		c.*2684A>G		3_prime_UTR	Exon 11 of 11	NP_001355959.1	O43307-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF9	ENST00000374878.5	TSL:1	c.1439A>G	p.Asn480Ser	missense	Exon 10 of 10	ENSP00000364012.2	B1AMR4
	ARHGEF9	ENST00000671741.2	MANE Select	c.*2684A>G		3_prime_UTR	Exon 10 of 10	ENSP00000500715.1	A0A5F9ZHY9
	ARHGEF9	ENST00000253401.10	TSL:1	c.*2684A>G		3_prime_UTR	Exon 10 of 10	ENSP00000253401.6	O43307-1

Frequencies

GnomAD3 genomes AF: 0.000143 AC: 16 AN: 111776 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00142

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000194 AC: 2 AN: 102990 AF XY: 0.00

Gnomad AFR exome AF: 0.000199

Gnomad AMR exome AF: 0.0000571

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000367 AC: 15 AN: 408554 Hom.: 0 Cov.: 0 AF XY: 0.0000269 AC XY: 4 AN XY: 148932

African (AFR) AF: 0.00 AC: 0 AN: 12236

American (AMR) AF: 0.000424 AC: 11 AN: 25918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14504

East Asian (EAS) AF: 0.00 AC: 0 AN: 23993

South Asian (SAS) AF: 0.00 AC: 0 AN: 36840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36493

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2956

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 232556

Other (OTH) AF: 0.000173 AC: 4 AN: 23058

GnomAD4 genome AF: 0.000143 AC: 16 AN: 111833 Hom.: 0 Cov.: 22 AF XY: 0.0000881 AC XY: 3 AN XY: 34033

African (AFR) AF: 0.0000325 AC: 1 AN: 30747

American (AMR) AF: 0.00142 AC: 15 AN: 10556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3546

South Asian (SAS) AF: 0.00 AC: 0 AN: 2646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6119

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53149

Other (OTH) AF: 0.00 AC: 0 AN: 1523

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000162

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy, 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.52
DANN	Benign	0.34
DEOGEN2	Benign	0.0076	T
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-0.85	T
PhyloP100		-0.74
REVEL	Benign	0.055
Sift4G	Benign	0.71	T
Vest4		0.092
MVP		0.26
ClinPred		0.0094	T
GERP RS		-2.5
Mutation Taster		=100/0	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: rs189661969; hg19: chrX-62855224; COSMIC: COSV53636209; COSMIC: COSV53636209;