Genetic Variant NM_001666.5:c.2768G>C (chrX-153907802-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001666.5(ARHGAP4):c.2768G>C(p.Arg923Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000446 in 896,290 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R923Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0000045 ( 0 hom. 1 hem. )

Consequence

ARHGAP4
NM_001666.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.353

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16715571).

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.2768G>C	p.Arg923Pro	missense	Exon 22 of 22	NP_001657.3
	ARHGAP4	NM_001164741.2		c.2888G>C	p.Arg963Pro	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.2768G>C	p.Arg923Pro	missense	Exon 22 of 22	ENSP00000203786.8	P98171-1
ARHGAP4	ENST00000370028.7	TSL:1	c.2888G>C	p.Arg963Pro	missense	Exon 23 of 23	ENSP00000359045.3	P98171-2
ENSG00000284987	ENST00000646191.1		n.96+1268G>C		intron	N/A	ENSP00000493873.1	A0A2R8Y4P6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

83783

AF XY:

0.0000337

show subpopulations

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:

0.0000232

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000446

AC:

AN:

896290

Hom.:

Cov.:

AF XY:

0.00000357

AC XY:

AN XY:

280092

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19651

American (AMR)

AF:

0.00

AC:

AN:

14530

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11678

East Asian (EAS)

AF:

0.00

AC:

AN:

23594

South Asian (SAS)

AF:

0.00

AC:

AN:

21118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31415

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3097

European-Non Finnish (NFE)

AF:

0.00000408

AC:

AN:

734976

Other (OTH)

AF:

0.0000276

AC:

AN:

36231

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000178

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.82

M_CAP

Benign

0.024

MetaRNN

Benign

0.17

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

-0.35

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.9

REVEL

Benign

0.11

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.017

Polyphen

0.90

Vest4

0.33

MutPred

0.28

Loss of MoRF binding (P = 0.002)

MVP

0.28

MPC

0.096

ClinPred

0.31

GERP RS

1.9

Varity_R

0.40

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over