Variant X-153907841-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001666.5(ARHGAP4):c.2729C>T(p.Pro910Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000355 in 1,013,930 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., 1 hem., cov: 25)

Exomes 𝑓: 0.000033 ( 0 hom. 5 hem. )

Consequence

ARHGAP4
NM_001666.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.25

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.039614767).

BS2

High Hemizygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP4	NM_001666.5 linkuse as main transcript	c.2729C>T	p.Pro910Leu	missense_variant	22/22	ENST00000350060.10
ARHGAP4	NM_001164741.2 linkuse as main transcript	c.2849C>T	p.Pro950Leu	missense_variant	23/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP4	ENST00000350060.10 linkuse as main transcript	c.2729C>T	p.Pro910Leu	missense_variant	22/22	1	NM_001666.5	P2	P98171-1

Frequencies

GnomAD3 genomes

AF:

0.0000531

AC:

AN:

112964

Hom.:

Cov.:

AF XY:

0.0000285

AC XY:

AN XY:

35122

show subpopulations

Gnomad AFR

AF:

0.000160

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:

0.000103

AC:

AN:

87459

Hom.:

AF XY:

0.0000950

AC XY:

AN XY:

31571

show subpopulations

Gnomad AFR exome

AF:

0.000519

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000496

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000443

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000333

AC:

AN:

900966

Hom.:

Cov.:

AF XY:

0.0000177

AC XY:

AN XY:

281774

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000593

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000217

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000531

AC:

AN:

112964

Hom.:

Cov.:

AF XY:

0.0000285

AC XY:

AN XY:

35122

show subpopulations

Gnomad4 AFR

AF:

0.000160

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:

0.000125

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000955

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

Feb 07, 2023

The c.2849C>T (p.P950L) alteration is located in exon 23 (coding exon 23) of the ARHGAP4 gene. This alteration results from a C to T substitution at nucleotide position 2849, causing the proline (P) at amino acid position 950 to be replaced by a leucine (L). 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

0.063

BayesDel_addAF

Benign

-0.87

BayesDel_noAF

Benign

-1.1

CADD

Benign

1.1

DANN

Benign

0.46

DEOGEN2

Benign

0.094

.;.;T;T

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.70

T;T;T;T

M_CAP

Benign

0.0049

MetaRNN

Benign

0.040

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.11

.;.;N;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Benign

0.0060

Sift

Benign

0.66

T;T;T;T

Sift4G

Benign

0.19

T;T;T;T

Polyphen

0.0010

.;.;B;.

Vest4

0.067

MVP

0.093

MPC

0.023

ClinPred

0.0065

GERP RS

-4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.030

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