rs1556365168

Variant names:

• chrX-63678411-A-G
• rs1556365168
• NM_001353921.2:c.744T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001353921.2(ARHGEF9):​c.744T>C​(p.Thr248Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,093,645 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: ARHGEF9 NM_001353921.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.570
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant X-63678411-A-G is Benign according to our data. Variant chrX-63678411-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 434306.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.57 with no splicing effect.

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.744T>C	p.Thr248Thr	synonymous	Exon 5 of 10	NP_001340850.1
	ARHGEF9	NM_001353923.1		c.762T>C	p.Thr254Thr	synonymous	Exon 5 of 10	NP_001340852.1
	ARHGEF9	NM_001369030.1		c.723T>C	p.Thr241Thr	synonymous	Exon 6 of 11	NP_001355959.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF9	ENST00000671741.2	MANE Select	c.744T>C	p.Thr248Thr	synonymous	Exon 5 of 10	ENSP00000500715.1
	ARHGEF9	ENST00000253401.10	TSL:1	c.723T>C	p.Thr241Thr	synonymous	Exon 5 of 10	ENSP00000253401.6
	ARHGEF9	ENST00000374878.5	TSL:1	c.744T>C	p.Thr248Thr	synonymous	Exon 5 of 10	ENSP00000364012.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1093645 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 359549

African (AFR) AF: 0.00 AC: 0 AN: 26341

American (AMR) AF: 0.00 AC: 0 AN: 34779

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19294

East Asian (EAS) AF: 0.00 AC: 0 AN: 30087

South Asian (SAS) AF: 0.00 AC: 0 AN: 53092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4123

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 839733

Other (OTH) AF: 0.00 AC: 0 AN: 45938

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 25, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.5
DANN	Benign	0.65
PhyloP100		-0.57

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: rs1556365168; hg19: chrX-62898291;