Genetic Variant ARHGAP4:p.Thr841Pro (chrX-153909156-T-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001666.5(ARHGAP4):c.2521A>C(p.Thr841Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,206,675 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 2 hem., cov: 24)

Exomes 𝑓: 0.000014 ( 0 hom. 7 hem. )

Consequence

ARHGAP4
NM_001666.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0990

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09162077).

BS2

High Hemizygotes in GnomAd4 at 2 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.2521A>C	p.Thr841Pro	missense	Exon 21 of 22	NP_001657.3
	ARHGAP4	NM_001164741.2		c.2641A>C	p.Thr881Pro	missense	Exon 22 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.2521A>C	p.Thr841Pro	missense	Exon 21 of 22	ENSP00000203786.8	P98171-1
ARHGAP4	ENST00000370028.7	TSL:1	c.2641A>C	p.Thr881Pro	missense	Exon 22 of 23	ENSP00000359045.3	P98171-2
ENSG00000284987	ENST00000646191.1		n.10A>C		non_coding_transcript_exon	Exon 1 of 5	ENSP00000493873.1	A0A2R8Y4P6

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112349

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:

0.0000377

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000574

AC:

AN:

174083

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000371

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:

0.0000137

AC:

AN:

1094326

Hom.:

Cov.:

AF XY:

0.0000194

AC XY:

AN XY:

360060

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26340

American (AMR)

AF:

0.0000571

AC:

AN:

35031

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19319

East Asian (EAS)

AF:

0.00

AC:

AN:

30093

South Asian (SAS)

AF:

0.00

AC:

AN:

53574

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4125

European-Non Finnish (NFE)

AF:

0.0000143

AC:

AN:

840583

Other (OTH)

AF:

0.0000218

AC:

AN:

45965

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000178

AC:

AN:

112349

Hom.:

Cov.:

AF XY:

0.0000579

AC XY:

AN XY:

34527

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30949

American (AMR)

AF:

0.00

AC:

AN:

10723

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3563

South Asian (SAS)

AF:

0.00

AC:

AN:

2739

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6194

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000377

AC:

AN:

53105

Other (OTH)

AF:

0.00

AC:

AN:

1515

Age Distribution

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.:

ExAC

AF:

0.00000824

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

0.056

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.91

CADD

Benign

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.13

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.44

M_CAP

Benign

0.0077

MetaRNN

Benign

0.092

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.69

PhyloP100

0.099

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.3

REVEL

Benign

0.034

Sift

Uncertain

0.0060

Sift4G

Benign

0.14

Polyphen

0.0

Vest4

0.25

MutPred

0.13

Loss of phosphorylation at T841 (P = 0.018)

MVP

0.20

MPC

0.025

ClinPred

0.053

GERP RS

-1.6

Varity_R

0.17

gMVP

0.29

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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