Genetic Variant ARHGAP36:c.-242C>G (chrX-131081832-C-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The ENST00000639280(ARHGAP36):c.-242C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000911 in 1,098,214 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000091 ( 0 hom. 4 hem. )

Consequence

ARHGAP36
ENST00000639280 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.46

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.40776488).

BS2

High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP36	NM_144967.4 link	c.167C>G	p.Ser56Cys	missense_variant	Exon 2 of 12	ENST00000276211.10	NP_659404.2	Q6ZRI8-1
ARHGAP36	NM_001282607.2 link	c.131C>G	p.Ser44Cys	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.167C>G	p.Ser56Cys	missense_variant	Exon 2 of 12	2	NM_144967.4	ENSP00000276211.5		Q6ZRI8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183416

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67848

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:

0.00

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.00000911

AC:

AN:

1098214

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

363570

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000568

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:

0.00000237

Gnomad4 OTH exome

AF:

0.000130

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000567

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.167C>G (p.S56C) alteration is located in exon 2 (coding exon 1) of the ARHGAP36 gene. This alteration results from a C to G substitution at nucleotide position 167, causing the serine (S) at amino acid position 56 to be replaced by a cysteine (C). 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

Uncertain

0.49

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

T;.;.;.

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.82

T;T;T;T

M_CAP

Benign

0.0087

MetaRNN

Benign

0.41

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

M;.;.;.

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-4.3

D;D;D;D

REVEL

Benign

0.21

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;.

Polyphen

1.0

D;D;.;D

Vest4

0.48

MutPred

0.59

Loss of disorder (P = 0.0016);.;.;.;

MVP

0.24

MPC

1.6

ClinPred

0.97

GERP RS

3.3

Varity_R

0.53

gMVP

0.44

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