NM_001353921.2:c.583-8dupT

Variant names:

• chrX-63678579-G-GA
• rs782366734
• NM_001353921.2:c.583-8dupT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001353921.2(ARHGEF9):​c.583-8dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,166,201 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000085 (0 hom. 2 hem.)
• Consequence: ARHGEF9 NM_001353921.2 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0570
• 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: Benign. The variant received -12 ACMG points.

• BP6: Variant X-63678579-G-GA is Benign according to our data. Variant chrX-63678579-G-GA is described in ClinVar as Likely_benign. ClinVar VariationId is 533664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF9	NM_001353921.2	MANE Select	c.583-8dupT		splice_region intron	N/A	NP_001340850.1
	ARHGEF9	NM_001353923.1		c.601-8dupT		splice_region intron	N/A	NP_001340852.1
	ARHGEF9	NM_001369030.1		c.562-8dupT		splice_region intron	N/A	NP_001355959.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF9	ENST00000671741.2	MANE Select	c.583-8_583-7insT		splice_region intron	N/A	ENSP00000500715.1
	ARHGEF9	ENST00000253401.10	TSL:1	c.562-8_562-7insT		splice_region intron	N/A	ENSP00000253401.6
	ARHGEF9	ENST00000374878.5	TSL:1	c.583-8_583-7insT		splice_region intron	N/A	ENSP00000364012.2

Frequencies

GnomAD3 genomes AF: 0.0000270 AC: 3 AN: 111112 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000980

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000143 AC: 2 AN: 139666 AF XY: 0.00

Gnomad AFR exome AF: 0.000101

Gnomad AMR exome AF: 0.00

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: 0.000269

GnomAD4 exome AF: 0.00000853 AC: 9 AN: 1055089 Hom.: 0 Cov.: 27 AF XY: 0.00000604 AC XY: 2 AN XY: 331229

African (AFR) AF: 0.000313 AC: 8 AN: 25542

American (AMR) AF: 0.00 AC: 0 AN: 31673

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18763

East Asian (EAS) AF: 0.00 AC: 0 AN: 29367

South Asian (SAS) AF: 0.00 AC: 0 AN: 50528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4042

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 811924

Other (OTH) AF: 0.0000225 AC: 1 AN: 44438

GnomAD4 genome AF: 0.0000270 AC: 3 AN: 111112 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33462

African (AFR) AF: 0.0000980 AC: 3 AN: 30597

American (AMR) AF: 0.00 AC: 0 AN: 10458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3549

South Asian (SAS) AF: 0.00 AC: 0 AN: 2640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5789

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53008

Other (OTH) AF: 0.00 AC: 0 AN: 1504

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Mar 16, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Developmental and epileptic encephalopathy, 8 Benign:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.057

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs782366734; hg19: chrX-62898459;