rs112475438
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
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
NM_001025616.3 missense
Scores
3
8
8
Clinical Significance
Conservation
PhyloP100: 9.29
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.04208663).
BS2
?
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARHGAP24 | NM_001025616.3 | 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 | c.473A>G | p.Gln158Arg | missense_variant | 5/10 | 2 | NM_001025616.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152150Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000446 AC: 112AN: 251158Hom.: 1 AF XY: 0.000354 AC XY: 48AN XY: 135712
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GnomAD4 exome AF: 0.0000869 AC: 127AN: 1461796Hom.: 2 Cov.: 33 AF XY: 0.0000729 AC XY: 53AN XY: 727202
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74344
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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 | 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). - |
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 | - - |
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.;.;T;.
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;.;.;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
T
PROVEAN
Benign
N;D;D;N;D;N;D
REVEL
Uncertain
Sift
Uncertain
D;T;T;D;T;D;D
Sift4G
Uncertain
D;T;T;D;T;D;D
Polyphen
D;D;.;D;.;.;P
Vest4
MutPred
Gain of MoRF binding (P = 0.0346);Gain of MoRF binding (P = 0.0346);.;.;.;.;.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at