chrX-63637846-CTGTGTG-C

Variant names:

• chrX-63637846-CTGTGTG-C
• rs10542660
• NM_001353921.2:c.*176_*181delCACACA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001353921.2(ARHGEF9):​c.*176_*181delCACACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 308,742 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 81 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., 53 hem., cov: 12)
  • Exomes 𝑓: 0.0023 (0 hom. 28 hem.)
• Consequence: ARHGEF9 NM_001353921.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.64
• Publications: 1 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 -4 ACMG points.

• BS2: High Hemizygotes in GnomAd4 at 53 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.*176_*181delCACACA		3_prime_UTR	Exon 10 of 10	NP_001340850.1	A0A5F9ZHY9
	ARHGEF9	NM_001353923.1		c.*176_*181delCACACA		3_prime_UTR	Exon 10 of 10	NP_001340852.1	A0A1B0GWI5
	ARHGEF9	NM_001369030.1		c.*176_*181delCACACA		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	ENST00000671741.2	MANE Select	c.*176_*181delCACACA		3_prime_UTR	Exon 10 of 10	ENSP00000500715.1	A0A5F9ZHY9
	ARHGEF9	ENST00000253401.10	TSL:1	c.*176_*181delCACACA		3_prime_UTR	Exon 10 of 10	ENSP00000253401.6	O43307-1
	ARHGEF9	ENST00000374878.5	TSL:1	c.1375-2444_1375-2439delCACACA		intron	N/A	ENSP00000364012.2	B1AMR4

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 215 AN: 97004 Hom.: 0 Cov.: 12

Gnomad AFR AF: 0.00641

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000799

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000318

Gnomad SAS AF: 0.00142

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00966

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00233

GnomAD4 exome AF: 0.00226 AC: 478 AN: 211726 Hom.: 0 AF XY: 0.000448 AC XY: 28 AN XY: 62522

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0278 AC: 177 AN: 6378

American (AMR) AF: 0.00171 AC: 14 AN: 8210

Ashkenazi Jewish (ASJ) AF: 0.00118 AC: 8 AN: 6785

East Asian (EAS) AF: 0.000755 AC: 13 AN: 17224

South Asian (SAS) AF: 0.00226 AC: 17 AN: 7520

European-Finnish (FIN) AF: 0.00122 AC: 18 AN: 14743

Middle Eastern (MID) AF: 0.00219 AC: 2 AN: 913

European-Non Finnish (NFE) AF: 0.00125 AC: 171 AN: 136749

Other (OTH) AF: 0.00439 AC: 58 AN: 13204

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00227 AC: 220 AN: 97016 Hom.: 0 Cov.: 12 AF XY: 0.00223 AC XY: 53 AN XY: 23770

African (AFR) AF: 0.00656 AC: 169 AN: 25766

American (AMR) AF: 0.000798 AC: 7 AN: 8767

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2390

East Asian (EAS) AF: 0.000319 AC: 1 AN: 3131

South Asian (SAS) AF: 0.00144 AC: 3 AN: 2090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4618

Middle Eastern (MID) AF: 0.0108 AC: 2 AN: 186

European-Non Finnish (NFE) AF: 0.000707 AC: 34 AN: 48121

Other (OTH) AF: 0.00307 AC: 4 AN: 1304

Alfa AF: 0.00 Hom.: 45

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs10542660; hg19: chrX-62857726;