Variant X-153909168-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001666.5(ARHGAP4):c.2509C>G(p.Pro837Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,201,931 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 9.2e-7 ( 0 hom. 1 hem. )

Consequence

ARHGAP4
NM_001666.5 missense, splice_region

Scores

Splicing: ADA: 0.0001098

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.190

Variant links:

Genes affected

ARHGAP4 (HGNC:674): (Rho GTPase activating protein 4) This gene encodes a member of the rhoGAP family of proteins which play a role in the regulation of small GTP-binding proteins belonging to the RAS superfamily. The protein encoded by the orthologous gene in rat is localized to the Golgi complex and can redistribute to microtubules. The rat protein stimulates the activity of some Rho GTPases in vitro. Genomic deletions of this gene and a neighboring gene have been found in patients with nephrogenic diabetes insipidus. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

ARHGAP4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07919347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP4	NM_001666.5 linkuse as main transcript	c.2509C>G	p.Pro837Ala	missense_variant, splice_region_variant	21/22	ENST00000350060.10	NP_001657.3
ARHGAP4	NM_001164741.2 linkuse as main transcript	c.2629C>G	p.Pro877Ala	missense_variant, splice_region_variant	22/23		NP_001158213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP4	ENST00000350060.10 linkuse as main transcript	c.2509C>G	p.Pro837Ala	missense_variant, splice_region_variant	21/22	1	NM_001666.5	ENSP00000203786	P2	P98171-1

Frequencies

GnomAD3 genomes

AF:

0.0000177

AC:

AN:

112767

Hom.:

Cov.:

AF XY:

0.0000286

AC XY:

AN XY:

34923

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.18e-7

AC:

AN:

1089164

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

355400

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000177

AC:

AN:

112767

Hom.:

Cov.:

AF XY:

0.0000286

AC XY:

AN XY:

34923

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:

0.0000376

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000825

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

May 04, 2023

The c.2629C>G (p.P877A) alteration is located in exon 22 (coding exon 22) of the ARHGAP4 gene. This alteration results from a C to G substitution at nucleotide position 2629, causing the proline (P) at amino acid position 877 to be replaced by an alanine (A). 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

0.065

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.87

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Benign

0.11

.;.;T;T

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.81

T;T;T;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.079

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.81

.;.;L;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.033

Sift

Benign

0.64

T;T;T;T

Sift4G

Benign

0.080

T;T;T;T

Polyphen

0.0090

.;.;B;.

Vest4

0.24

MutPred

0.16

.;.;Gain of relative solvent accessibility (P = 0.0479);.;

MVP

0.26

MPC

0.026

ClinPred

0.037

GERP RS

-0.15

Varity_R

0.032

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00011

dbscSNV1_RF

Benign

0.056

SpliceAI score (max)

0.39

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.39

Position offset: -4

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