rs781823638

Positions:

chrX-63724576-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001353921.2(ARHGEF9):c.166C>A(p.Gln56Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000397 in 1,208,796 control chromosomes in the GnomAD database, including 1 homozygotes. There are 28 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000042 ( 1 hom. 28 hem. )

Consequence

ARHGEF9
NM_001353921.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 6.43

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.067786574).

BP6

Variant X-63724576-G-T is Benign according to our data. Variant chrX-63724576-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434308.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000181 (2/110656) while in subpopulation SAS AF= 0.000779 (2/2566). AF 95% confidence interval is 0.000138. There are 0 homozygotes in gnomad4. There are 0 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAdExome4 at 28 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF9	NM_001353921.2 linkuse as main transcript	c.166C>A	p.Gln56Lys	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.166C>A	p.Gln56Lys	missense_variant	2/10		NM_001353921.2	ENSP00000500715	A1

Frequencies

GnomAD3 genomes

AF:

0.0000181

AC:

AN:

110656

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32902

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:

0.000779

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000109

AC:

AN:

182944

Hom.:

AF XY:

0.000193

AC XY:

AN XY:

67484

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000997

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000419

AC:

AN:

1098140

Hom.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

363500

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000794

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000181

AC:

AN:

110656

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32902

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:

0.000779

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000181

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 27, 2016

- -

Developmental and epileptic encephalopathy, 8

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.062

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

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;D;D;.;D;.;.;.;D;.;D;.;.;.;D;D;D;D;D;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.068

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.55

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

MutationTaster

Benign

1.0

D;D;D;D;D

PROVEAN

Benign

0.58

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

REVEL

Benign

0.15

Sift

Benign

0.21

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

Sift4G

Benign

0.27

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

Polyphen

0.012

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

Vest4

0.26

MutPred

0.55

Gain of ubiquitination at Q49 (P = 0.0128);.;Gain of ubiquitination at Q49 (P = 0.0128);.;.;.;.;.;.;.;.;.;.;.;.;Gain of ubiquitination at Q49 (P = 0.0128);.;.;.;.;

MVP

0.76

MPC

1.3

ClinPred

0.14

GERP RS

5.5

Varity_R

0.60

gMVP

0.89

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