chrX-63724693-T-C

Position:

chrX-63724693-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001353921.2(ARHGEF9):c.49A>G(p.Ile17Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,209,553 control chromosomes in the GnomAD database, including 1 homozygotes. There are 48 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., 30 hem., cov: 22)

Exomes 𝑓: 0.000087 ( 0 hom. 18 hem. )

Consequence

ARHGEF9
NM_001353921.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.35

Variant links:

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 links:

ARHGEF9 (HGNC:):

ARHGEF9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00862357).

BP6

Variant X-63724693-T-C is Benign according to our data. Variant chrX-63724693-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 128450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-63724693-T-C is described in Lovd as [Benign]. Variant chrX-63724693-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00116 (129/111530) while in subpopulation AFR AF= 0.00411 (126/30665). AF 95% confidence interval is 0.00353. There are 1 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 30 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF9	NM_001353921.2 linkuse as main transcript	c.49A>G	p.Ile17Val	missense_variant	2/10	ENST00000671741.2	NP_001340850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF9	ENST00000671741.2 linkuse as main transcript	c.49A>G	p.Ile17Val	missense_variant	2/10		NM_001353921.2	ENSP00000500715.1		A0A5F9ZHY9

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

129

AN:

111474

Hom.:

Cov.:

AF XY:

0.000891

AC XY:

AN XY:

33652

show subpopulations

Gnomad AFR

AF:

0.00412

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000284

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

GnomAD3 exomes

AF:

0.000218

AC:

AN:

183125

Hom.:

AF XY:

0.0000740

AC XY:

AN XY:

67609

show subpopulations

Gnomad AFR exome

AF:

0.00296

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000865

AC:

AN:

1098023

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

363389

show subpopulations

Gnomad4 AFR exome

AF:

0.00326

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.000108

GnomAD4 genome

AF:

0.00116

AC:

129

AN:

111530

Hom.:

Cov.:

AF XY:

0.000890

AC XY:

AN XY:

33718

show subpopulations

Gnomad4 AFR

AF:

0.00411

Gnomad4 AMR

AF:

0.000284

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000123

Hom.:

Bravo

AF:

0.00122

ESP6500AA

AF:

0.00469

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000222

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 26, 2018	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 29, 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. -

Developmental and epileptic encephalopathy, 8

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.83

CADD

Benign

DANN

Benign

0.43

DEOGEN2

Benign

0.070

T;T;.;.;.;T

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.81

T;T;T;T;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.0086

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.41

N;.;.;.;.;.

PROVEAN

Benign

0.67

N;.;.;.;.;.

REVEL

Benign

0.048

Sift

Benign

1.0

T;.;.;.;.;.

Sift4G

Benign

1.0

T;T;T;T;.;.

Polyphen

0.0

B;.;.;.;.;.

Vest4

0.17

MVP

0.45

MPC

0.84

ClinPred

0.0074

GERP RS

4.0

Varity_R

0.090

gMVP

0.78

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over