rs782508508

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.2018C>T(p.Pro673Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000571 in 1,208,366 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 25 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000044 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000058 ( 0 hom. 24 hem. )

Consequence

ARHGAP4
NM_001666.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.79

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:

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=0.27368802).

BS2

High Hemizygotes in GnomAdExome4 at 24 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP4	NM_001666.5 link	c.2018C>T	p.Pro673Leu	missense_variant	Exon 17 of 22	ENST00000350060.10	NP_001657.3	P98171-1
ARHGAP4	NM_001164741.2 link	c.2138C>T	p.Pro713Leu	missense_variant	Exon 18 of 23		NP_001158213.1	P98171-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP4	ENST00000350060.10 link	c.2018C>T	p.Pro673Leu	missense_variant	Exon 17 of 22	1	NM_001666.5	ENSP00000203786.8		P98171-1

Frequencies

GnomAD3 genomes

AF:

0.0000444

AC:

AN:

112500

Hom.:

Cov.:

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:

0.0000941

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000623

AC:

AN:

176613

AF XY:

0.0000783

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000111

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000742

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000128

Gnomad OTH exome

AF:

0.000230

GnomAD4 exome

AF:

0.0000584

AC:

AN:

1095866

Hom.:

Cov.:

AF XY:

0.0000663

AC XY:

AN XY:

362098

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26378

American (AMR)

AF:

0.000114

AC:

AN:

35099

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19265

East Asian (EAS)

AF:

0.0000332

AC:

AN:

30157

South Asian (SAS)

AF:

0.000204

AC:

AN:

53936

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4128

European-Non Finnish (NFE)

AF:

0.0000499

AC:

AN:

841330

Other (OTH)

AF:

0.000109

AC:

AN:

45987

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.0000444

AC:

AN:

112500

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34668

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31000

American (AMR)

AF:

0.00

AC:

AN:

10730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3545

South Asian (SAS)

AF:

0.00

AC:

AN:

2736

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6247

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000941

AC:

AN:

53153

Other (OTH)

AF:

0.00

AC:

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 19, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2138C>T (p.P713L) alteration is located in exon 18 (coding exon 18) of the ARHGAP4 gene. This alteration results from a C to T substitution at nucleotide position 2138, causing the proline (P) at amino acid position 713 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

0.16

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

.;.;T;T

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.27

T;T;T;T

MetaSVM

Benign

-0.30

MutationAssessor

Pathogenic

3.1

.;.;M;.

PhyloP100

1.8

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-4.7

D;D;D;D

REVEL

Benign

0.091

Sift

Benign

0.19

T;T;T;T

Sift4G

Uncertain

0.043

D;D;D;D

Polyphen

0.21

.;.;B;.

Vest4

0.35

MutPred

0.41

.;.;Gain of stability (P = 0.0242);.;

MVP

0.37

MPC

0.16

ClinPred

0.37

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.48

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over