X-153907905-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_001666.5(ARHGAP4):c.2665C>T(p.Arg889Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,063,953 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R889P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., 5 hem., cov: 25)

Exomes 𝑓: 0.000018 ( 0 hom. 3 hem. )

Consequence

ARHGAP4
NM_001666.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.63

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

intellectual disability
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ARHGAP4 links:

ENSG00000284987 (HGNC:):

ENSG00000284987 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30213988).

BS2

High Hemizygotes in GnomAd4 at 5 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001666.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP4	NM_001666.5	MANE Select	c.2665C>T	p.Arg889Cys	missense	Exon 22 of 22	NP_001657.3
	ARHGAP4	NM_001164741.2		c.2785C>T	p.Arg929Cys	missense	Exon 23 of 23	NP_001158213.1	P98171-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGAP4	ENST00000350060.10	TSL:1 MANE Select	c.2665C>T	p.Arg889Cys	missense	Exon 22 of 22	ENSP00000203786.8	P98171-1
ARHGAP4	ENST00000370028.7	TSL:1	c.2785C>T	p.Arg929Cys	missense	Exon 23 of 23	ENSP00000359045.3	P98171-2
ENSG00000284987	ENST00000646191.1		n.96+1165C>T		intron	N/A	ENSP00000493873.1	A0A2R8Y4P6

Frequencies

GnomAD3 genomes

AF:

0.000142

AC:

AN:

112386

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000931

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

95981

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000179

AC:

AN:

951567

Hom.:

Cov.:

AF XY:

0.0000101

AC XY:

AN XY:

296915

show subpopulations

African (AFR)

AF:

0.000293

AC:

AN:

20451

American (AMR)

AF:

0.00

AC:

AN:

17940

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13173

East Asian (EAS)

AF:

0.0000832

AC:

AN:

24048

South Asian (SAS)

AF:

0.00

AC:

AN:

32147

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3533

European-Non Finnish (NFE)

AF:

0.0000118

AC:

AN:

765913

Other (OTH)

AF:

0.00

AC:

AN:

38944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000142

AC:

AN:

112386

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

AN XY:

34572

show subpopulations

African (AFR)

AF:

0.000485

AC:

AN:

30944

American (AMR)

AF:

0.0000931

AC:

AN:

10746

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3548

South Asian (SAS)

AF:

0.00

AC:

AN:

2737

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6228

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53091

Other (OTH)

AF:

0.00

AC:

AN:

1519

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000102

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000837

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

FATHMM_MKL

Benign

0.39

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.043

MetaRNN

Benign

0.30

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

2.6

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.089

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.047

Polyphen

1.0

Vest4

0.38

MVP

0.20

MPC

0.14

ClinPred

0.94

GERP RS

0.99

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.23

gMVP

0.44

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over