Variant X-131086055-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_144967.4(ARHGAP36):c.1247G>A(p.Arg416His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000314 in 1,209,245 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000028 ( 0 hom. 8 hem. )

Consequence

ARHGAP36
NM_144967.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.14

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=0.16515744).

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ARHGAP36	NM_144967.4 linkuse as main transcript	c.1247G>A	p.Arg416His	missense_variant	9/12	ENST00000276211.10
ARHGAP36	NM_001282607.2 linkuse as main transcript	c.1211G>A	p.Arg404His	missense_variant	9/12
ARHGAP36	NM_001330651.1 linkuse as main transcript	c.839G>A	p.Arg280His	missense_variant	8/11
ARHGAP36	XM_011531280.2 linkuse as main transcript	c.839G>A	p.Arg280His	missense_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP36	ENST00000276211.10 linkuse as main transcript	c.1247G>A	p.Arg416His	missense_variant	9/12	2	NM_144967.4	P4	Q6ZRI8-1

Frequencies

GnomAD3 genomes

AF:

0.0000627

AC:

AN:

111656

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

33850

show subpopulations

Gnomad AFR

AF:

0.000195

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000328

AC:

AN:

182652

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

67110

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000144

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000367

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000282

AC:

AN:

1097589

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

362947

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.0000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000285

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000627

AC:

AN:

111656

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

33850

show subpopulations

Gnomad4 AFR

AF:

0.000195

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:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2021

The c.1247G>A (p.R416H) alteration is located in exon 9 (coding exon 8) of the ARHGAP36 gene. This alteration results from a G to A substitution at nucleotide position 1247, causing the arginine (R) at amino acid position 416 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

0.13

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;.;.;.;.

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.83

T;T;T;T;.

M_CAP

Benign

0.0067

MetaRNN

Benign

0.17

T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.0

L;.;.;.;.

MutationTaster

Benign

0.67

D;D;D

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.9

N;N;.;N;N

REVEL

Benign

0.12

Sift

Benign

0.066

T;T;.;T;T

Sift4G

Uncertain

0.035

D;T;.;.;D

Polyphen

0.013

B;B;.;B;.

Vest4

0.20

MVP

0.16

MPC

0.80

ClinPred

0.065

GERP RS

3.8

Varity_R

0.14

gMVP

0.83

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