Genetic Variant ARHGAP36:p.Arg45Leu (chrX-131081799-G-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_144967.4(ARHGAP36):c.134G>T(p.Arg45Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000578 in 1,210,405 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R45S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000061 ( 0 hom. 18 hem. )

Consequence

ARHGAP36
NM_144967.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.328

Variant links:

Genes affected

ARHGAP36 (HGNC:26388): (Rho GTPase activating protein 36) Predicted to enable GTPase activator activity. Predicted to be involved in regulation of catalytic activity and signal transduction. [provided by Alliance of Genome Resources, Apr 2022]

ARHGAP36 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0625751).

BS2

High Hemizygotes in GnomAdExome4 at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP36	NM_144967.4 link	c.134G>T	p.Arg45Leu	missense_variant	Exon 2 of 12	ENST00000276211.10	NP_659404.2	Q6ZRI8-1
ARHGAP36	NM_001282607.2 link	c.98G>T	p.Arg33Leu	missense_variant	Exon 2 of 12		NP_001269536.1	Q6ZRI8-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP36	ENST00000276211.10 link	c.134G>T	p.Arg45Leu	missense_variant	Exon 2 of 12	2	NM_144967.4	ENSP00000276211.5		Q6ZRI8-1

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112168

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34346

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:

0.0000563

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

183438

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67870

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000610

AC:

AN:

1098237

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

363591

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

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:

0.0000760

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112168

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34346

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:

0.0000563

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 29, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.134G>T (p.R45L) alteration is located in exon 2 (coding exon 1) of the ARHGAP36 gene. This alteration results from a G to T substitution at nucleotide position 134, causing the arginine (R) at amino acid position 45 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.76

CADD

Benign

2.4

DANN

Benign

0.89

DEOGEN2

Benign

0.018

T;.;.

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.64

T;T;T

M_CAP

Benign

0.0034

MetaRNN

Benign

0.063

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.1

L;.;.

PrimateAI

Benign

0.32

PROVEAN

Benign

1.1

N;N;N

REVEL

Benign

0.026

Sift

Uncertain

0.0040

D;D;D

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

0.45

B;B;B

Vest4

0.26

MVP

0.043

MPC

0.74

ClinPred

0.057

GERP RS

1.4

Varity_R

0.068

gMVP

0.27

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