chrX-63638129-C-A

Variant names:

• chrX-63638129-C-A
• rs782577519
• NM_001353921.2:c.1471G>T

Variant summary

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

The NM_001353921.2(ARHGEF9):​c.1471G>T​(p.Asp491Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000183 in 1,093,709 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. D491N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: ARHGEF9 NM_001353921.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.68
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF9	NM_001353921.2	c.1471G>T	p.Asp491Tyr	missense_variant	Exon 10 of 10	ENST00000671741.2	NP_001340850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF9	ENST00000671741.2	c.1471G>T	p.Asp491Tyr	missense_variant	Exon 10 of 10		NM_001353921.2	ENSP00000500715.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1093709 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 359461

African (AFR) AF: 0.00 AC: 0 AN: 26343

American (AMR) AF: 0.00 AC: 0 AN: 34786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19325

East Asian (EAS) AF: 0.00 AC: 0 AN: 30061

South Asian (SAS) AF: 0.00 AC: 0 AN: 53040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40219

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4131

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 839869

Other (OTH) AF: 0.00 AC: 0 AN: 45935

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.;T;T;T;T;T;T;.;T;.;T;T;.;T;.;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;.;D;.;.;.;D;.;D;.;.;D;.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.5	L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		5.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.0	N;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.015	D;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Sift4G	Benign	0.26	T;D;.;.;.;.;.;.;T;T;.;.;.;.;T;T;.
Polyphen		0.93	P;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.42
MutPred		0.42		Loss of solvent accessibility (P = 0.0152);Loss of solvent accessibility (P = 0.0152);.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.82
MPC		2.0
ClinPred		0.89	D
GERP RS		5.5
Varity_R		0.53
gMVP		0.83
Mutation Taster		=42/58	disease causing

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: rs782577519; hg19: chrX-62858009;