Genetic Variant ARHGAP36:p.Asn42Lys (chrX-131081791-C-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.126C>A(p.Asn42Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000454 in 1,210,503 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 20 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 0.000053 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000045 ( 0 hom. 18 hem. )

Consequence

ARHGAP36
NM_144967.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.291

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=0.07016283).

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP36	NM_144967.4 link	c.126C>A	p.Asn42Lys	missense_variant	Exon 2 of 12	ENST00000276211.10	NP_659404.2	Q6ZRI8-1
ARHGAP36	NM_001282607.2 link	c.90C>A	p.Asn30Lys	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.126C>A	p.Asn42Lys	missense_variant	Exon 2 of 12	2	NM_144967.4	ENSP00000276211.5		Q6ZRI8-1

Frequencies

GnomAD3 genomes

AF:

0.0000535

AC:

AN:

112210

Hom.:

Cov.:

AF XY:

0.0000582

AC XY:

AN XY:

34390

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000188

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:

0.000670

GnomAD3 exomes

AF:

0.0000763

AC:

AN:

183472

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

67900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000109

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000854

Gnomad OTH exome

AF:

0.000662

GnomAD4 exome

AF:

0.0000446

AC:

AN:

1098241

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

363595

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.000170

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000554

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000356

Gnomad4 OTH exome

AF:

0.0000868

GnomAD4 genome

AF:

0.0000534

AC:

AN:

112262

Hom.:

Cov.:

AF XY:

0.0000581

AC XY:

AN XY:

34452

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000187

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:

0.000661

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.126C>A (p.N42K) alteration is located in exon 2 (coding exon 1) of the ARHGAP36 gene. This alteration results from a C to A substitution at nucleotide position 126, causing the asparagine (N) at amino acid position 42 to be replaced by a lysine (K). 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

0.17

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.81

CADD

Benign

3.9

DANN

Uncertain

0.99

DEOGEN2

Benign

0.026

T;.;.

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.74

T;T;T

M_CAP

Benign

0.0059

MetaRNN

Benign

0.070

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;.;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.12

N;N;N

REVEL

Benign

0.046

Sift

Benign

0.080

T;T;T

Sift4G

Benign

0.36

T;T;.

Polyphen

0.76

P;P;P

Vest4

0.15

MutPred

0.28

Gain of methylation at N42 (P = 0.0062);.;.;

MVP

0.13

MPC

1.1

ClinPred

0.035

GERP RS

1.3

Varity_R

0.068

gMVP

0.28

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