Genetic Variant ARHGAP36:p.Arg149His (chrX-131083860-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_144967.4(ARHGAP36):c.446G>A(p.Arg149His) variant causes a missense change. The variant allele was found at a frequency of 0.0000429 in 1,210,944 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000035 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000044 ( 0 hom. 9 hem. )

Consequence

ARHGAP36
NM_144967.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.08

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11328629).

BS2

High Hemizygotes in GnomAdExome4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP36	NM_144967.4 link	c.446G>A	p.Arg149His	missense_variant	Exon 4 of 12	ENST00000276211.10	NP_659404.2	Q6ZRI8-1
ARHGAP36	NM_001282607.2 link	c.410G>A	p.Arg137His	missense_variant	Exon 4 of 12		NP_001269536.1	Q6ZRI8-4
ARHGAP36	NM_001330651.1 link	c.38G>A	p.Arg13His	missense_variant	Exon 3 of 11		NP_001317580.1	Q6ZRI8-3
ARHGAP36	XM_011531280.2 link	c.38G>A	p.Arg13His	missense_variant	Exon 3 of 11		XP_011529582.1	Q6ZRI8-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP36	ENST00000276211.10 link	c.446G>A	p.Arg149His	missense_variant	Exon 4 of 12	2	NM_144967.4	ENSP00000276211.5		Q6ZRI8-1

Frequencies

GnomAD3 genomes

AF:

0.0000355

AC:

AN:

112641

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34777

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:

0.0000750

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000437

AC:

AN:

1098250

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

363606

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

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:

0.0000487

Gnomad4 OTH exome

AF:

0.000130

GnomAD4 genome

AF:

0.0000355

AC:

AN:

112694

Hom.:

Cov.:

AF XY:

0.0000287

AC XY:

AN XY:

34840

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:

0.0000750

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.446G>A (p.R149H) alteration is located in exon 4 (coding exon 3) of the ARHGAP36 gene. This alteration results from a G to A substitution at nucleotide position 446, causing the arginine (R) at amino acid position 149 to be replaced by a histidine (H). 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

0.11

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.031

T;.;.;.;.;.

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.89

D;D;D;D;D;.

M_CAP

Benign

0.0068

MetaRNN

Benign

0.11

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;.;.;.;.;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.55

N;N;N;.;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.011

D;D;T;.;D;D

Sift4G

Benign

0.071

T;T;D;.;.;D

Polyphen

1.0

D;D;.;.;D;.

Vest4

0.098

MVP

0.27

MPC

0.74

ClinPred

0.32

GERP RS

3.5

Varity_R

0.11

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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