rs143490560

Positions:

chrX-63674044-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001353921.2(ARHGEF9):c.939C>G(p.Asp313Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000485 in 1,209,430 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 190 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 0.00024 ( 0 hom., 7 hem., cov: 23)

Exomes 𝑓: 0.00051 ( 0 hom. 183 hem. )

Consequence

ARHGEF9
NM_001353921.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.60

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11057103).

BP6

Variant X-63674044-G-C is Benign according to our data. Variant chrX-63674044-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 383604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-63674044-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000241 (27/111955) while in subpopulation NFE AF= 0.000508 (27/53192). AF 95% confidence interval is 0.000358. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF9	NM_001353921.2 linkuse as main transcript	c.939C>G	p.Asp313Glu	missense_variant	6/10	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.939C>G	p.Asp313Glu	missense_variant	6/10		NM_001353921.2	ENSP00000500715	A1

Frequencies

GnomAD3 genomes

AF:

0.000241

AC:

AN:

111902

Hom.:

Cov.:

AF XY:

0.000205

AC XY:

AN XY:

34074

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000508

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000350

AC:

AN:

182813

Hom.:

AF XY:

0.000297

AC XY:

AN XY:

67407

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000267

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000631

Gnomad NFE exome

AF:

0.000724

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000509

AC:

559

AN:

1097475

Hom.:

Cov.:

AF XY:

0.000504

AC XY:

183

AN XY:

363085

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000103

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.000640

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000241

AC:

AN:

111955

Hom.:

Cov.:

AF XY:

0.000205

AC XY:

AN XY:

34137

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000508

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000531

Hom.:

Bravo

AF:

0.000302

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000743

AC:

ExAC

AF:

0.000264

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000653

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

ARHGEF9-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 02, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 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

Dec 16, 2019

This variant is associated with the following publications: (PMID: 22581972) -

Developmental and epileptic encephalopathy, 8

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

T;T;.;T;T;T;T;T;T;.;.;T;.;T;T;.;T;.;T;T;.

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.79

T;T;T;T;.;T;.;.;.;T;T;.;T;.;.;T;.;T;T;T;T

M_CAP

Benign

0.052

MetaRNN

Benign

0.11

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.8

L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.3

N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;.;.

REVEL

Uncertain

0.32

Sift

Benign

0.080

T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.

Sift4G

Benign

0.081

T;T;T;.;.;.;.;.;.;T;T;T;.;.;.;.;T;T;.;.;.

Polyphen

0.38

B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.26

MutPred

0.49

Gain of helix (P = 0.0696);.;Gain of helix (P = 0.0696);.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of helix (P = 0.0696);.;

MVP

0.91

MPC

0.98

ClinPred

0.045

GERP RS

2.9

Varity_R

0.36

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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