Genetic Variant NM_001666.5:c.2729C>T (chrX-153907841-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 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

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: Benign. The variant received -8 ACMG points.

BP4

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

BS2

High Hemizygotes in GnomAdExome4 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.2729C>T	p.Pro910Leu	missense	Exon 22 of 22	NP_001657.3
	ARHGAP4	NM_001164741.2		c.2849C>T	p.Pro950Leu	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.2729C>T	p.Pro910Leu	missense	Exon 22 of 22	ENSP00000203786.8	P98171-1
ARHGAP4	ENST00000370028.7	TSL:1	c.2849C>T	p.Pro950Leu	missense	Exon 23 of 23	ENSP00000359045.3	P98171-2
ENSG00000284987	ENST00000646191.1		n.96+1229C>T		intron	N/A	ENSP00000493873.1	A0A2R8Y4P6

Frequencies

GnomAD3 genomes

AF:

0.0000531

AC:

AN:

112964

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000103

AC:

AN:

87459

AF XY:

0.0000950

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 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

African (AFR)

AF:

0.00

AC:

AN:

19673

American (AMR)

AF:

0.00

AC:

AN:

14538

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11776

East Asian (EAS)

AF:

0.000593

AC:

AN:

23604

South Asian (SAS)

AF:

0.00

AC:

AN:

22153

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32025

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3302

European-Non Finnish (NFE)

AF:

0.0000217

AC:

AN:

737409

Other (OTH)

AF:

0.00

AC:

AN:

36486

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.0000531

AC:

AN:

112964

Hom.:

Cov.:

AF XY:

0.0000285

AC XY:

AN XY:

35122

show subpopulations

African (AFR)

AF:

0.000160

AC:

AN:

31158

American (AMR)

AF:

0.00

AC:

AN:

10829

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3565

South Asian (SAS)

AF:

0.00

AC:

AN:

2798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53202

Other (OTH)

AF:

0.00

AC:

AN:

1530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.555

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:

0.0000712

Hom.:

Bravo

AF:

0.000125

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000955

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

0.063

BayesDel_addAF

Benign

-0.87

BayesDel_noAF

Benign

-1.1

CADD

Benign

1.1

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.094

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.70

M_CAP

Benign

0.0049

MetaRNN

Benign

0.040

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.11

PhyloP100

-1.2

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.2

REVEL

Benign

0.0060

Sift

Benign

0.66

Sift4G

Benign

0.19

Polyphen

0.0010

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

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