22-44786576-G-A

Position:

chr22-44786576-G-A

Variant summary

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

The ENST00000356099.11(ARHGAP8):c.49G>A(p.Val17Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,613,302 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 2 hom. )

Consequence

ARHGAP8
ENST00000356099.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.45

Variant links:

Genes affected

ARHGAP8 (HGNC:677): (Rho GTPase activating protein 8) This gene encodes a member of the RHOGAP family. GAP (GTPase-activating) family proteins participate in signaling pathways that regulate cell processes involved in cytoskeletal changes. GAP proteins alternate between an active (GTP-bound) and inactive (GDP-bound) state based on the GTP:GDP ratio in the cell. This family member is a multidomain protein that functions to promote Erk activation and cell motility. Alternative splicing results in multiple transcript variants. Read-through transcripts from the upstream proline rich 5, renal (PRR5) gene into this gene also exist, which led to the original description of PRR5 and ARHGAP8 being a single gene. [provided by RefSeq, Nov 2010]

ARHGAP8 links:

PRR5-ARHGAP8 (HGNC:):

PRR5-ARHGAP8 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=0.048265666).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ARHGAP8	NM_181335.3 linkuse as main transcript	c.49G>A	p.Val17Met	missense_variant	2/12	ENST00000356099.11	NP_851852.2
PRR5-ARHGAP8	NM_181334.6 linkuse as main transcript	c.442G>A	p.Val148Met	missense_variant	5/15		NP_851851.3
ARHGAP8	NM_001017526.2 linkuse as main transcript	c.49G>A	p.Val17Met	missense_variant	2/13		NP_001017526.1
ARHGAP8	NM_001198726.2 linkuse as main transcript	c.49G>A	p.Val17Met	missense_variant	2/11		NP_001185655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP8	ENST00000356099.11 linkuse as main transcript	c.49G>A	p.Val17Met	missense_variant	2/12	1	NM_181335.3	ENSP00000348407	P1	P85298-4

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000276

AC:

AN:

246528

Hom.:

AF XY:

0.000247

AC XY:

AN XY:

133842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00170

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.000230

Gnomad FIN exome

AF:

0.000278

Gnomad NFE exome

AF:

0.000319

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000180

AC:

263

AN:

1461124

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

126

AN XY:

726812

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00172

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.000432

Gnomad4 NFE exome

AF:

0.000148

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000342

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000409

Hom.:

Bravo

AF:

0.000212

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000280

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

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

Jan 31, 2022

The c.49G>A (p.V17M) alteration is located in exon 2 (coding exon 1) of the ARHGAP8 gene. This alteration results from a G to A substitution at nucleotide position 49, causing the valine (V) at amino acid position 17 to be replaced by a methionine (M). 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

0.51

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.074

.;.;T;T;.;.;T

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.22

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.97

D;D;D;D;D;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.048

T;T;T;T;T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Pathogenic

3.2

.;.;M;.;M;M;.

MutationTaster

Benign

0.68

N;N;N;N;N;N;N

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.8

N;N;N;N;N;N;N

REVEL

Benign

0.13

Sift

Uncertain

0.026

D;T;D;D;D;D;D

Sift4G

Uncertain

0.034

D;T;D;T;D;D;D

Polyphen

1.0

D;D;P;.;.;.;.

Vest4

0.55

MVP

0.20

ClinPred

0.16

GERP RS

3.5

Varity_R

0.11

gMVP

0.66

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