rs112475438

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001025616.3(ARHGAP24):c.473A>G(p.Gln158Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000824 in 1,613,946 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000087 ( 2 hom. )

Consequence

ARHGAP24
NM_001025616.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 9.29

Variant links:

Genes affected

ARHGAP24 (HGNC:25361): (Rho GTPase activating protein 24) This gene encodes a Rho-GTPase activating protein, which is specific for the small GTPase family member Rac. Binding of the encoded protein by filamin A targets it to sites of membrane protrusion, where it antognizes Rac. This results in suppression of lamellae formation and promotion of retraction to regulate cell polarity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

ARHGAP24 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04208663).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP24	NM_001025616.3 linkuse as main transcript	c.473A>G	p.Gln158Arg	missense_variant	5/10	ENST00000395184.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP24	ENST00000395184.6 linkuse as main transcript	c.473A>G	p.Gln158Arg	missense_variant	5/10	2	NM_001025616.3	P1	Q8N264-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.000446

AC:

112

AN:

251158

Hom.:

AF XY:

0.000354

AC XY:

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00321

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:

0.000163

GnomAD4 exome

AF:

0.0000869

AC:

127

AN:

1461796

Hom.:

Cov.:

AF XY:

0.0000729

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00284

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000393

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:

0.000136

Hom.:

Bravo

AF:

0.000166

ExAC

AF:

0.000338

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2017	The Q158R (c.473 A>G) variant in the ARHGAP24 gene was initially reported in an Hispanic individual with familial focal segmental glomerulosclerosis and was also identified in his affected sister and mother. This variant was not present in another sister with a history of pregnancy-related proteinuria and hypertension, who did not have renal biopsy to fully evaluate her affected status (Akilesh et al., 2011). The Q158R (c.473 A>G) variant is observed in 41/11510 (0.37%) alleles from individuals of Latino background, including one homozygote, in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In-silico splice prediction models predict that this variant (c.473 A>G) may create a cryptic splice donor site in exon 5 that could supplant the natural splice donor site. However, in the absence of RNA/functional studies, the actual effect of the c.473 A>G change in this individual is unknown. If c.473 A>G does not alter splicing, it will result in the Q158R missense change, which is a semi-conservative amino acid substitution. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Studies of an orthologous variant in mice (Q156R) demonstrate that this variant reduces the enzymatic activity of the Arhgap24 protein (Akilesh et al., 2011). Given the available evidence, we interpret Q158R (c.473 A>G) as a variant of uncertain significance. -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Mar 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 09, 2023	Experimental studies have shown that this missense change affects ARHGAP24 function (PMID: 21911940). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬† is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 224509). This missense change has been observed in individual(s) with clinical features of ARHGAP24-related conditions (PMID: 21911940, 30406062). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs112475438, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 158 of the ARHGAP24 protein (p.Gln158Arg). -

ARHGAP24-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 24, 2024

The ARHGAP24 c.473A>G variant is predicted to result in the amino acid substitution p.Gln158Arg. This variant was reported in the heterozygous state to segregate with end-stage kidney disease and focal segmental glomerulosclerosis in a family with three affected and two unaffected individuals, and functional assays demonstrated reduced ARHGAP24 enzymatic activity (Akilesh et al. 2011. PubMed ID: 21911940). This variant was also reported in the heterozygous state in two unrelated individuals with steroid-resistant nephrotic syndrome (Table S2, Varner et al. 2018. PubMed ID: 30406062). This variant is reported in 0.32% of alleles in individuals of Latino descent in gnomAD, including one homozygous individual. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Uncertain

0.12

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.058

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

Eigen

Uncertain

0.63

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D;D;D;D;D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.042

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

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.40

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

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.3

N;D;D;N;D;N;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.0090

D;T;T;D;T;D;D

Sift4G

Uncertain

0.027

D;T;T;D;T;D;D

Polyphen

1.0

D;D;.;D;.;.;P

Vest4

0.93

MutPred

0.58

Gain of MoRF binding (P = 0.0346);Gain of MoRF binding (P = 0.0346);.;.;.;.;.;

MVP

0.62

MPC

0.22

ClinPred

0.14

GERP RS

6.0

Varity_R

0.48

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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