rs782580975

chrX-63638112-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001353921.2(ARHGEF9):c.1488G>A(p.Ser496=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,206,575 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 47 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., 5 hem., cov: 22)
  • Exomes 𝑓: 0.00013 (0 hom. 42 hem.)
• Consequence: ARHGEF9 NM_001353921.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.45

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant X-63638112-C-T is Benign according to our data. Variant chrX-63638112-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 465078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-63638112-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.45 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000144 (16/111098) while in subpopulation AMR AF= 0.000578 (6/10389). AF 95% confidence interval is 0.000251. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF9	NM_001353921.2	c.1488G>A	p.Ser496=	synonymous_variant	10/10	ENST00000671741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF9	ENST00000671741.2	c.1488G>A	p.Ser496=	synonymous_variant	10/10		NM_001353921.2	A1

Frequencies

GnomAD3 genomes AF: 0.000144 AC: 16 AN: 111052 Hom.: 0 Cov.: 22 AF XY: 0.000150 AC XY: 5 AN XY: 33268

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000578

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000281

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000151

Gnomad OTH AF: 0.000664

GnomAD3 exomes AF: 0.000125 AC: 22 AN: 176384 Hom.: 0 AF XY: 0.0000814 AC XY: 5 AN XY: 61442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000556

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000741

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000767

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000131 AC: 143 AN: 1095477 Hom.: 0 Cov.: 31 AF XY: 0.000116 AC XY: 42 AN XY: 360999

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000829

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000124

Gnomad4 OTH exome AF: 0.000152

GnomAD4 genome AF: 0.000144 AC: 16 AN: 111098 Hom.: 0 Cov.: 22 AF XY: 0.000150 AC XY: 5 AN XY: 33324

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000578

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000282

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000151

Gnomad4 OTH AF: 0.000655

Alfa AF: 0.000285 Hom.: 1

Bravo AF: 0.000325

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 23, 2020

- -

Developmental and epileptic encephalopathy, 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 07, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	2.1
Dann	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs782580975; hg19: chrX-62857992;